Methods for treating vascular leak syndrome

ABSTRACT

Disclosed are methods for treating Vascular Leak Syndrome. Further disclosed are methods for treating vascular leakage due to inflammatory diseases, inter alia, sepsis, lupus, inflammatory bowel disease. Yet further disclosed are methods for treating renal cell carcinoma and melanoma. Still further disclosed are methods for reducing metastasis of malignant cells and/or preventing the proliferation of carcinoma cells via spreading due to vascular leakage.

CROSS REFERENCE TO RELATED APPLICATIONS

This application is a Divisional Application of application Ser. No.12/677,512 filed Mar. 22, 2010, which is a U.S. National StageApplication under 35 U.S.C. 371(c) of PCT/US2010/020817, filed Jan. 12,2010, which claims the benefit of Provisional Application Ser. No.61/144,022 filed on Jan. 12, 2009 and Provisional Application Ser. No.61/184,985 filed on Jun. 8, 2009. The entire disclosure of thesereferenced applications is incorporated herein by reference.

FIELD

Disclosed are methods for treating Vascular Leak Syndrome. Furtherdisclosed are methods for treating vascular leakage due to inflammatorydiseases, inter alia, sepsis, lupus, inflammatory bowel disease. Alsodisclosed are methods for treating vascular leakage due to the presenceof pathogens. Yet further disclosed are methods for treating metastaticrenal cell carcinoma and metastatic melanoma.

BACKGROUND

Vascular leak is characterized by hypotension, peripheral edema, andhypoalbuminemia. Vascular leak can occur as a side effect of illnessespecially illnesses due to pathogens, inter alia, viruses and bacteria.Vascular leak complicates the healing process and can itself be a directresult of certain therapies. For example, patients suffering frommalignant renal carcinoma are given Interleukin-2 to help boost theirimmune system; however, this treatment must be withdrawn in manypatients due to the onset of severe vascular leak well before the fullcourse of treatment can be administered. Therefore, the cancer treatmentis withdrawn earlier than desired and usually before the therapy ismaximally effective. VLS restricts the doses of IL-2 which can beadministered to humans and, in some cases, necessitates the cessation oftherapy.

VLS is characterized by an increase in vascular permeability accompaniedby extravasation of fluids and proteins resulting in interstitial edemaand organ failure. Manifestations of VLS include fluid retention,increase in body weight, peripheral edema, pleural and pericardialeffusions, ascites, anasarca and, in severe form, signs of pulmonary andcardiovascular failure. Symptoms are highly variable among patients andthe causes are poorly understood. Endothelial cell modifications ordamage are thought to be important is vascular leak. The pathogenesis ofendothelial cell (EC) damage is complex and can involve activation ordamage to ECs and leukocytes, release of cytokines and of inflammatorymediators, alteration in cell-cell and cell-matrix adhesion and incytoskeleton function.

During the course of antiviral and antibacterial infections, patientscan develop vascular leak that is induced as result of the initialinfection. There is now a long felt need for a method of preventingvascular leak due to viral or bacterial infection, and therefore providea method of increasing the survival of humans or other mammals infectedwith one or more pathogens. In addition, there is a long felt need for amethod of preventing vascular leakage due to certain anticancer drugs orother anticancer therapies such that the administration of anticancerdrugs or anticancer therapies can be given to humans or other mammalsfor a longer course of treatment or therapy.

SUMMARY

Disclosed herein are compounds that inhibit the intracellular catalyticsite of human protein tyrosine phosphatase beta (HPTP-β) molecule.HPTP-β is known only to be expressed in vascular endothelial cells.Inhibition of HPTP-β reduces the rate of dephosphorylation of the Tie-2receptor tyrosine kinase. This inhibition results in amplification ofthe Angiopoietin 1 (Ang-1) signal through Tie-2, and effectivelycounters the inhibitory effects of Angiopoietin 2 (Ang-2) on Tie-2.Because Tie-2 is critical to maintaining vascular endothelial integrity,the disclosed HPTP-β inhibitors provide a method for providing vascularstabilization in humans and mammals. As such, the disclosed HPTP-βinhibitors provide Tie-2 signal amplification. One importantmanifestation of vascular de-stabilization is vascular leak syndrome(VLS) which has many causes, for example, infection of a human or mammalby a pathogen. Another common cause of vascular leak syndrome is the useof certain chemotherapeutic agents, inter alia, IL-2 which is used intreating certain forms of cancer.

Disclosed herein are methods for stabilizing human and mammalianvasculature. The stabilization of vasculature in patients compromisedwith an infection due to the presence of pathogens, inter alia,bacteria, viruses, yeasts, and fungi, provide a method for preventingcomplications due to infection such as sepsis, pulmonary edema, and thelike. Subjects suffering from or diagnosed with certain cancers aregiven chemotherapeutic agents that result in vascular leak syndrome as aprimary side effect causing cessation of treatment before the desiredfull course has been achieved. For weakened humans and mammals, theonset of vascular leak syndrome due to one or more compromising eventscan be avoided by the disclosed methods for monitoring the level ofAng-2 and administering the appropriate amount of HPTP-β inhibitor,either alone, or as part of a prophylactic combination therapy.

BRIEF DESCRIPTION OF THE FIGURES

FIG. 1 depicts the effect of4-{(S)-2-[(S)-2-(methoxycarbonylamino)-3-phenyl-propanamido]-2-[2-(thiophen-2-yl)thiazol-4-yl]ethyl}phenylsulfamicacid ammonium salt (inhibitor) on murine blood pressure during IL-2induced VLS at low and high IL-2 dosing. As depicted, High IL-2 dosingin the absence of a Tie-2 signal amplifier resulted in death. A depictsthe control sample; B depicts mice treated with 180,000 IU of IL-2 for 5days; C depicts mice treated with 180,000 IU of IL-2 for 5 days and 40mg/kg of D91 for the first 2 days, then at 20 mg/kg for 3 days; Ddepicts mice treated with 400,000 IU of IL-2 for 5 days; E depicts micetreated with 400,000 IU of IL-2 for 5 days and 40 mg/kg of D91 for thefirst 2 days, then at 20 mg/kg for 3 days.

FIG. 2 depicts the effect of4-{(S)-2-[(S)-2-(methoxycarbonylamino)-3-phenyl-propanamido]-2-[2-(thiophen-2-yl)thiazol-4-yl]ethyl}phenylsulfamicacid ammonium salt, a Tie-2 signal amplifier, on IL-2 induced shock inmice. A depicts the control sample; B depicts mice treated with 180,000IU of IL-2 for 5 days; C depicts mice treated with 180,000 IU of IL-2for 5 days and 40 mg/kg of D91 for the first 2 days, then at 20 mg/kgfor 3 days; D depicts mice treated with 400,000 IU of IL-2 for 5 days; Edepicts mice treated with 400,000 IU of IL-2 for 5 days and 40 mg/kg ofD91 for the first 2 days, then at 20 mg/kg for 3 days.

FIG. 3 depicts the effect of4-{(S)-2-[(S)-2-(methoxycarbonylamino)-3-phenyl-propanamido]-2-[2-(thiophen-2-yl)thiazol-4-yl]ethyl}phenylsulfamicacid ammonium salt, a Tie-2 signal amplifier, on IL-2 induced murinemortality. A depicts the control sample; B depicts mice treated with180,000 IU of IL-2 for 5 days; C depicts mice treated with 180,000 IU ofIL-2 for 5 days and 40 mg/kg of D91 for the first 2 days, then at 20mg/kg for 3 days; D depicts mice treated with 400,000 IU of IL-2 for 5days; E depicts mice treated with 400,000 IU of IL-2 for 5 days and 40mg/kg of D91 for the first 2 days, then at 20 mg/kg for 3 days.

FIG. 4 depicts the status of the animals of each group after treatmentwith High IL-2 dosing with and without the Tie-2 signal amplifier,4-{(S)-2-[(S)-2-(methoxycarbonylamino)-3-phenyl-propanamido]-2-[2-(thiophen-2-yl)thiazol-4-yl]ethyl}phenylsulfamicacid ammonium salt. A depicts the control sample; B depicts the statusof mice treated with 400,000 IU of IL-2 for 5 days; C depicts status ofmice treated with 400,000 IU of IL-2 for 5 days and 40 mg/kg of D91 forthe first 2 days, then at 20 mg/kg for 3 days.

FIG. 5 depicts the rescue of mice from IL-2 induced hypotension anddeath. A represents the systolic blood pressure of C3H/HeN female micetreated with vehicle control. B represents the systolic blood pressureof C3H/HeN female mice treated with 400,000 IU of IL-2. C represents thesystolic blood pressure of C3H/HeN female mice treated with 400,000 IUof IL-2 and 40 mg/kg of compound D91. Measurements were taken after 5days of treatment.

FIG. 6 depicts mice (4/group) that were treated with 400,000 IU of IL-2in combination with various doses of D91 over 5 days. A represents 0mg/kg D91, B represents 1 mg/kg D91, C represents 3 mg/kg D91, Drepresents 10 mg/kg D91, and E represents 30 mg/kg D91.

FIG. 7 depicts the level of blood urine nitrogen (BUN) in male C57BL6mice injected i.p. with 0.2 mg E. coli lipopolysaccharides per 25 g bodyweight at 0 hours. Line (◯) represents mice receiving only LPS and line(●) represents mice receiving LPS and 50 mg/kg of D91 at 0, 8, and 16hours.

FIG. 8 depicts the level of LPS-induced renal neutrophil infiltration at24 hours in male C57BL6 mice injected i.p. with 0.2 mg E. colilipopolysaccharides per 25 g body weight at 0 hours. A depicts theneutrophil infiltration in sham (conrol), B depicts the neutrophilinfiltration in male C57BL6 mice injected i.p. with 0.2 mg E. colilipopolysaccharides per 25 g body weight and 50 mg/kg of D91, C depictsmice receiving only LPS.

FIG. 9 a depicts a Western blot analysis showing the increase in pAKTand pERK1/2 when EA.hy962 cells were cultured in the presence of varyingamounts of D91 for 10 minutes.

FIG. 9 b depicts a Western blot analysis showing the levels of pAKT,pERK1/2 and β-Actin when EA.hy962 cells were cultured in the presence of10 μg/mL D91 from start (T=0) to 120 minutes.

FIG. 10 a is a micrograph of a renal section from a mouse treated withvehicle control that is subsequently injected with 70 kDa fluorescentfixable dextran by intravenous catheter 2 minutes prior to sacrifice. Gindicates glomerular capillaries where the dye should normally becontained.

FIG. 10 b is a micrograph showing the vascular leakage in cells of arenal section from a mouse treat with LPS that is subsequently injectedwith 70 kDa fluorescent fixable dextran by intravenous catheter 2minutes prior to sacrifice. The 70 kDa fluorescent dextran is nowsignificantly located in the interstitial space between the capillariesand the cells.

FIG. 10 c is a micrograph showing that vascular integrity is preservedas compared to LPS treatment for cells in a renal section from a mousetreated with LPS and D91 that is subsequently injected with 70 kDa offluorescent fixable dextran by intravenous catheter 2 minutes prior tosacrifice. The pattern of staining in this section is similar to 10a.

DETAILED DESCRIPTION

The materials, compounds, compositions, articles, and methods describedherein may be understood more readily by reference to the followingdetailed description of specific aspects of the disclosed subject matterand the Examples included therein.

Before the present materials, compounds, compositions, articles,devices, and methods are disclosed and described, it is to be understoodthat the aspects described below are not limited to specific syntheticmethods or specific reagents, as such may, of course, vary. It is alsoto be understood that the terminology used herein is for the purpose ofdescribing particular aspects only and is not intended to be limiting.

Also, throughout this specification, various publications arereferenced. The disclosures of these publications in their entiretiesare hereby incorporated by reference into this application in order tomore fully describe the state of the art to which the disclosed matterpertains. The references disclosed are also individually andspecifically incorporated by reference herein for the material containedin them that is discussed in the sentence in which the reference isrelied upon.

General Definitions

In this specification and in the claims that follow, reference will bemade to a number of terms, which shall be defined to have the followingmeanings:

All percentages, ratios and proportions herein are by weight, unlessotherwise specified. All temperatures are in degrees Celsius (° C.)unless otherwise specified.

By “pharmaceutically acceptable” is meant a material that is notbiologically or otherwise undesirable, i.e., the material can beadministered to an individual along with the relevant active compoundwithout causing clinically unacceptable biological effects orinteracting in a deleterious manner with any of the other components ofthe pharmaceutical composition in which it is contained.

Ranges may be expressed herein as from “about” one particular value,and/or to “about” another particular value. When such a range isexpressed, another aspect includes from the one particular value and/orto the other particular value. Similarly, when values are expressed asapproximations, by use of the antecedent “about,” it will be understoodthat the particular value forms another aspect. It will be furtherunderstood that the endpoints of each of the ranges are significant bothin relation to the other endpoint, and independently of the otherendpoint.

A weight percent of a component, unless specifically stated to thecontrary, is based on the total weight of the formulation or compositionin which the component is included.

By “effective amount” as used herein means “an amount of one or more ofthe disclosed Tie-2 signal amplifiers, effective at dosages and forperiods of time necessary to achieve the desired or therapeutic result.”An effective amount may vary according to factors known in the art, suchas the disease state, age, sex, and weight of the human or animal beingtreated. Although particular dosage regimes may be described in examplesherein, a person skilled in the art would appreciated that the dosageregime may be altered to provide optimum therapeutic response. Forexample, several divided doses may be administered daily or the dose maybe proportionally reduced as indicated by the exigencies of thetherapeutic situation. In addition, the compositions of this disclosurecan be administered as frequently as necessary to achieve a therapeuticamount.

“Admixture” or “blend” is generally used herein means a physicalcombination of two or more different components

“Excipient” is used herein to include any other compound that may becontained in or combined with one or more of the disclosed inhibitorsthat is not a therapeutically or biologically active compound. As such,an excipient should be pharmaceutically or biologically acceptable orrelevant (for example, an excipient should generally be non-toxic to thesubject). “Excipient” includes a single such compound and is alsointended to include a plurality of excipients.

As used herein, by a “subject” is meant an individual. Thus, the“subject” can include domesticated animals (e.g., cats, dogs, etc.),livestock (e.g., cattle, horses, pigs, sheep, goats, etc.), laboratoryanimals (e.g., mouse, rabbit, rat, guinea pig, etc.), and birds.“Subject” can also include a mammal, such as a primate or a human.

By “reduce” or other forms of the word, such as “reducing” or“reduction,” is meant lowering of an event or characteristic (e.g.,vascular leakage). It is understood that this is typically in relationto some standard or expected value, in other words it is relative, butthat it is not always necessary for the standard or relative value to bereferred to.

By “prevent” or other forms of the word, such as “preventing” or“prevention,” is meant to stop a particular event or characteristic, tostabilize or delay the development or progression of a particular eventor characteristic, or to minimize the chances that a particular event orcharacteristic will occur. Prevent does not require comparison to acontrol as it is typically more absolute than, for example, reduce. Asused herein, something could be reduced but not prevented, but somethingthat is reduced could also be prevented. Likewise, something could beprevented but not reduced, but something that is prevented could also bereduced. It is understood that where reduce or prevent are used, unlessspecifically indicated otherwise, the use of the other word is alsoexpressly disclosed.

By “treat” or other forms of the word, such as “treated” or “treatment,”is meant to administer a composition or to perform a method in order toreduce, prevent, inhibit, break-down, or eliminate a particularcharacteristic or event (e.g., vascular leakge). The disclosed compoundsaffect vascular leakage by inhibiting HPTP-β (and the rodent equivalent,VE-PTP) which enhances or amplifies Tie-2 signaling.

By “chemotherapeutic agent” is meant any drug, pharmaceutical orotherwise, that can be given to a subject as part of a combinationtherapy. Non-limiting examples of chemotherapeutic agents includeanticancer drugs, for example, IL-2, taxol, and the like,antimicrobials, anti-virals, anti-fungicides, and the like.

Throughout the description and claims of this specification the word“comprise” and other forms of the word, such as “comprising” and“comprises,” means including but not limited to, and is not intended toexclude, for example, other additives, components, integers, or steps.

As used in the description and the appended claims, the singular forms“a,” “an,” and “the” include plural referents unless the context clearlydictates otherwise. Thus, for example, reference to “a composition”includes mixtures of two or more such compositions, reference to “aphenylsulfamic acid” includes mixtures of two or more suchphenylsulfamic acids, reference to “the compound” includes mixtures oftwo or more such compounds, and the like.

“Optional” or “optionally” means that the subsequently described eventor circumstance can or cannot occur, and that the description includesinstances where the event or circumstance occurs and instances where itdoes not.

Ranges can be expressed herein as from “about” one particular value,and/or to “about” another particular value. When such a range isexpressed, another aspect includes from the one particular value and/orto the other particular value. Similarly, when values are expressed asapproximations, by use of the antecedent “about,” it will be understoodthat the particular value forms another aspect. It will be furtherunderstood that the endpoints of each of the ranges are significant bothin relation to the other endpoint, and independently of the otherendpoint. It is also understood that there are a number of valuesdisclosed herein, and that each value is also herein disclosed as“about” that particular value in addition to the value itself. Forexample, if the value “10” is disclosed, then “about 10” is alsodisclosed. It is also understood that when a value is disclosed, then“less than or equal to” the value, “greater than or equal to the value,”and possible ranges between values are also disclosed, as appropriatelyunderstood by the skilled artisan. For example, if the value “10” isdisclosed, then “less than or equal to 10” as well as “greater than orequal to 10” is also disclosed. It is also understood that throughoutthe application data are provided in a number of different formats andthat this data represent endpoints and starting points and ranges forany combination of the data points. For example, if a particular datapoint “10” and a particular data point “15” are disclosed, it isunderstood that greater than, greater than or equal to, less than, lessthan or equal to, and equal to 10 and 15 are considered disclosed aswell as between 10 and 15. It is also understood that each unit betweentwo particular units are also disclosed. For example, if 10 and 15 aredisclosed, then 11, 12, 13, and 14 are also disclosed.

The following chemical hierarchy is used throughout the specification todescribe and enable the scope of the present disclosure and toparticularly point out and distinctly claim the units which comprise thecompounds of the present disclosure, however, unless otherwisespecifically defined, the terms used herein are the same as those of theartisan of ordinary skill. The term “hydrocarbyl” stands for any carbonatom-based unit (organic molecule), said units optionally containing oneor more organic functional group, including inorganic atom comprisingsalts, inter alia, carboxylate salts, quaternary ammonium salts. Withinthe broad meaning of the term “hydrocarbyl” are the classes “acyclichydrocarbyl” and “cyclic hydrocarbyl” which terms are used to dividehydrocarbyl units into cyclic and non-cyclic classes.

As it relates to the following definitions, “cyclic hydrocarbyl” unitscan comprise only carbon atoms in the ring (i.e., carbocyclic and arylrings) or can comprise one or more heteroatoms in the ring (i.e.,heterocyclic and heteroaryl rings). For “carbocyclic” rings the lowestnumber of carbon atoms in a ring are 3 carbon atoms; cyclopropyl. For“aryl” rings the lowest number of carbon atoms in a ring are 6 carbonatoms; phenyl. For “heterocyclic” rings the lowest number of carbonatoms in a ring is 1 carbon atom; diazirinyl. Ethylene oxide comprises 2carbon atoms and is a C₂ heterocycle. For “heteroaryl” rings the lowestnumber of carbon atoms in a ring is 1 carbon atom; 1,2,3,4-tetrazolyl.The following is a non-limiting description of the terms “acyclichydrocarbyl” and “cyclic hydrocarbyl” as used herein.

-   A. Substituted and unsubstituted acyclic hydrocarbyl:    -   For the purposes of the present disclosure the term “substituted        and unsubstituted acyclic hydrocarbyl” encompasses 3 categories        of units:-   1) linear or branched alkyl, non-limiting examples of which include,    methyl (C₁), ethyl (C₂), n-propyl (C₃), iso-propyl (C₃), n-butyl    (C₄), sec-butyl (C₄), iso-butyl (C₄), tert-butyl (C₄), and the like;    substituted linear or branched alkyl, non-limiting examples of which    includes, hydroxymethyl (C₁), chloromethyl (C₁), trifluoromethyl    (C₁), aminomethyl (C₁), 1-chloroethyl (C₂), 2-hydroxyethyl (C₂),    1,2-difluoroethyl (C₂), 3-carboxypropyl (C₃), and the like.-   2) linear or branched alkenyl, non-limiting examples of which    include, ethenyl (C₂), 3-propenyl (C₃), 1-propenyl (also    2-methylethenyl) (C₃), isopropenyl (also 2-methylethen-2-yl) (C₃),    buten-4-yl (C₄), and the like; substituted linear or branched    alkenyl, non-limiting examples of which include, 2-chloroethenyl    (also 2-chlorovinyl) (C₂), 4-hydroxybuten-1-yl (C₄),    7-hydroxy-7-methyloct-4-en-2-yl (C₉),    7-hydroxy-7-methyloct-3,5-dien-2-yl (C₉), and the like.-   3) linear or branched alkynyl, non-limiting examples of which    include, ethynyl (C₂), prop-2-ynyl (also propargyl) (C₃),    propyn-1-yl (C₃), and 2-methyl-hex-4-yn-1-yl (C₇); substituted    linear or branched alkynyl, non-limiting examples of which include,    5-hydroxy-5-methylhex-3-ynyl (C₇), 6-hydroxy-6-methylhept-3-yn-2-yl    (C₈), 5-hydroxy-5-ethylhept-3-ynyl (C₉), and the like.-   B. Substituted and unsubstituted cyclic hydrocarbyl:    -   For the purposes of the present disclosure the term “substituted        and unsubstituted cyclic hydrocarbyl” encompasses 5 categories        of units:-   1) The term “carbocyclic” is defined herein as “encompassing rings    comprising from 3 to 20 carbon atoms, wherein the atoms which    comprise said rings are limited to carbon atoms, and further each    ring can be independently substituted with one or more moieties    capable of replacing one or more hydrogen atoms.” The following are    non-limiting examples of “substituted and unsubstituted carbocyclic    rings” which encompass the following categories of units:    -   i) carbocyclic rings having a single substituted or        unsubstituted hydrocarbon ring, non-limiting examples of which        include, cyclopropyl (C₃), 2-methyl-cyclopropyl (C₃),        cyclopropenyl (C₃), cyclobutyl (C₄), 2,3-dihydroxycyclobutyl        (C₄), cyclobutenyl (C₄), cyclopentyl (C₅), cyclopentenyl (C₅),        cyclopentadienyl (C₅), cyclohexyl (C₆), cyclohexenyl (C₆),        cycloheptyl (C₇), cyclooctanyl (C₈), 2,5-dimethylcyclopentyl        (C₅), 3,5-dichlorocyclohexyl (C₆), 4-hydroxycyclohexyl (C₆), and        3,3,5-trimethylcyclohex-1-yl (C₆).    -   ii) carbocyclic rings having two or more substituted or        unsubstituted fused hydrocarbon rings, non-limiting examples of        which include, octahydropentalenyl (C₈), octahydro-1H-indenyl        (C₉), 3a,4,5,6,7,7a-hexahydro-3H-inden-4-yl (C₉),        decahydroazulenyl (C₁₀).    -   iii) carbocyclic rings which are substituted or unsubstituted        bicyclic hydrocarbon rings, non-limiting examples of which        include, bicyclo-[2.1.1]hexanyl, bicyclo[2.2.1]heptanyl,        bicyclo[3.1.1]heptanyl, 1,3-dimethyl[2.2.1]heptan-2-yl,        bicyclo[2.2.2]octanyl, and bicyclo[3.3.3]undecanyl.-   2) The term “aryl” is defined herein as “units encompassing at least    one phenyl or naphthyl ring and wherein there are no heteroaryl or    heterocyclic rings fused to the phenyl or naphthyl ring and further    each ring can be independently substituted with one or more moieties    capable of replacing one or more hydrogen atoms.” The following are    non-limiting examples of “substituted and unsubstituted aryl rings”    which encompass the following categories of units:    -   i) C₆ or C₁₀ substituted or unsubstituted aryl rings; phenyl and        naphthyl rings whether substituted or unsubstituted,        non-limiting examples of which include, phenyl (C₆),        naphthylen-1-yl (C₁₀), naphthylen-2-yl (C₁₀), 4-fluorophenyl        (C₆), 2-hydroxyphenyl (C₆), 3-methylphenyl (C₆),        2-amino-4-fluorophenyl (C₆), 2-(N,N-diethylamino)phenyl (C₆),        2-cyanophenyl (C₆), 2,6-di-tert-butylphenyl (C₆),        3-methoxyphenyl (C₆), 8-hydroxynaphthylen-2-yl (C₁₀),        4,5-dimethoxynaphthylen-1-yl (C₁₀), and 6-cyano-naphthylen-1-yl        (C₁₀).    -   ii) C₆ or C₁₀ aryl rings fused with 1 or 2 saturated rings to        afford C₈-C₂₀ ring systems, non-limiting examples of which        include, bicyclo[4.2.0]octa-1,3,5-trienyl (C₈), and indanyl        (C₉).-   3) The terms “heterocyclic” and/or “heterocycle” are defined herein    as “units comprising one or more rings having from 3 to 20 atoms    wherein at least one atom in at least one ring is a heteroatom    chosen from nitrogen (N), oxygen (O), or sulfur (S), or mixtures of    N, O, and S, and wherein further the ring which contains the    heteroatom is also not an aromatic ring.” The following are    non-limiting examples of “substituted and unsubstituted heterocyclic    rings” which encompass the following categories of units:    -   i) heterocyclic units having a single ring containing one or        more heteroatoms, non-limiting examples of which include,        diazirinyl (C₁), aziridinyl (C₂), urazolyl (C₂), azetidinyl        (C₃), pyrazolidinyl (C₃), imidazolidinyl (C₃), oxazolidinyl        (C₃), isoxazolinyl (C₃), thiazolidinyl (C₃), isothiazolinyl        (C₃), oxathiazolidinonyl (C₃), oxazolidinonyl (C₃), hydantoinyl        (C₃), tetrahydrofuranyl (C₄), pyrrolidinyl (C₄), morpholinyl        (C₄), piperazinyl (C₄), piperidinyl (C₄), dihydropyranyl (C₅),        tetrahydropyranyl (C₅), piperidin-2-onyl (valerolactam) (C₅),        2,3,4,5-tetrahydro-1H-azepinyl (C₆), 2,3-dihydro-1H-indole (C₈),        and 1,2,3,4-tetrahydroquinoline (C₉).    -   ii) heterocyclic units having 2 or more rings one of which is a        heterocyclic ring, non-limiting examples of which include        hexahydro-1H-pyrrolizinyl (C₇),        3a,4,5,6,7,7a-hexahydro-1H-benzo[d]imidazolyl (C₇),        3a,4,5,6,7,7a-hexahydro-1H-indolyl (C₈),        1,2,3,4-tetrahydroquinolinyl (C₉), and        decahydro-1H-cycloocta[b]pyrrolyl (C₁₀).-   4) The term “heteroaryl” is defined herein as “encompassing one or    more rings comprising from 5 to 20 atoms wherein at least one atom    in at least one ring is a heteroatom chosen from nitrogen (N),    oxygen (O), or sulfur (S), or mixtures of N, O, and S, and wherein    further at least one of the rings which comprises a heteroatom is an    aromatic ring.” The following are non-limiting examples of    “substituted and unsubstituted heterocyclic rings” which encompass    the following categories of units:    -   i) heteroaryl rings containing a single ring, non-limiting        examples of which include, 1,2,3,4-tetrazolyl (C₁),        [1,2,3]triazolyl (C₂), [1,2,4]triazolyl (C₂), triazinyl (C₃),        thiazolyl (C₃), 1H-imidazolyl (C₃), oxazolyl (C₃), isoxazolyl        (C₃), isothiazolyl (C₃), furanyl (C₄), thiophenyl (C₄),        pyrimidinyl (C₄), 2-phenylpyrimidinyl (C₄), pyridinyl (C₅),        3-methylpyridinyl (C₅), and 4-dimethylaminopyridinyl (C₅)    -   ii) heteroaryl rings containing 2 or more fused rings one of        which is a heteroaryl ring, non-limiting examples of which        include: 7H-purinyl (C₅), 9H-purinyl (C₅), 6-amino-9H-purinyl        (C₅), 5H-pyrrolo[3,2-d]pyrimidinyl (C₆),        7H-pyrrolo[2,3-d]pyrimidinyl (C₆), pyrido[2,3-d]pyrimidinyl        (C₇), 2-phenylbenzo[d]thiazolyl (C₇), 1H-indolyl (C₈),        4,5,6,7-tetrahydro-1-H-indolyl (C₈), quinoxalinyl (C₈),        5-methylquinoxalinyl (C₈), quinazolinyl (C₈), quinolinyl (C₉),        8-hydroxy-quinolinyl (C₉), and isoquinolinyl (C₉).-   5) C₁-C₆ tethered cyclic hydrocarbyl units (whether carbocyclic    units, C₆ or C₁₀ aryl units, heterocyclic units, or heteroaryl    units) which connected to another moiety, unit, or core of the    molecule by way of a C₁-C₆ alkylene unit. Non-limiting examples of    tethered cyclic hydrocarbyl units include benzyl C₁-(C₆) having the    formula:

-   -   wherein R^(a) is optionally one or more independently chosen        substitutions for hydrogen. Further examples include other aryl        units, inter alia, (2-hydroxyphenyl)hexyl C₆-(C₆);        naphthalen-2-ylmethyl C₁-(C₁₀), 4-fluorobenzyl C₁-(C₆),        2-(3-hydroxyphenyl)ethyl C₂-(C₆), as well as substituted and        unsubstituted C₃-C₁₀ alkylenecarbocyclic units, for example,        cyclopropylmethyl C₁-(C₃), cyclopentylethyl C₂-(C₅),        cyclohexylmethyl C₁-(C₆). Included within this category are        substituted and unsubstituted C₁-C₁₀ alkylene-heteroaryl units,        for example a 2-picolyl C₁-(C₆) unit having the formula:

-   -   wherein R^(a) is the same as defined above. In addition, C₁-C₁₂        tethered cyclic hydrocarbyl units include C₁-C₁₀        alkyleneheterocyclic units and alkylene-heteroaryl units,        non-limiting examples of which include, aziridinylmethyl C₁-(C₂)        and oxazol-2-ylmethyl C₁-(C₃).

For the purposes of the present disclosure carbocyclic rings are from C₃to C₂₀; aryl rings are C₆ or C₁₀; heterocyclic rings are from C₁ to C₉;and heteroaryl rings are from C₁ to C₉.

For the purposes of the present disclosure, and to provide consistencyin defining the present disclosure, fused ring units, as well asspirocyclic rings, bicyclic rings and the like, which comprise a singleheteroatom will be characterized and referred to herein as beingencompassed by the cyclic family corresponding to the heteroatomcontaining ring, although the artisan may have alternativecharacterizations. For example, 1,2,3,4-tetrahydroquinoline having theformula:

is, for the purposes of the present disclosure, considered aheterocyclic unit. 6,7-Dihydro-5H-cyclopentapyrimidine having theformula:

is, for the purposes of the present disclosure, considered a heteroarylunit. When a fused ring unit contains heteroatoms in both a saturatedring (heterocyclic ring) and an aryl ring (heteroaryl ring), the arylring will predominate and determine the type of category to which thering is assigned herein for the purposes of describing the invention.For example, 1,2,3,4-tetrahydro-[1,8]naphthpyridine having the formula:

is, for the purposes of the present disclosure, considered a heteroarylunit.

The term “substituted” is used throughout the specification. The term“substituted” is applied to the units described herein as “substitutedunit or moiety is a hydrocarbyl unit or moiety, whether acyclic orcyclic, which has one or more hydrogen atoms replaced by a substituentor several substituents as defined herein below.” The units, whensubstituting for hydrogen atoms are capable of replacing one hydrogenatom, two hydrogen atoms, or three hydrogen atoms of a hydrocarbylmoiety at a time. In addition, these substituents can replace twohydrogen atoms on two adjacent carbons to form said substituent, newmoiety, or unit. For example, a substituted unit that requires a singlehydrogen atom replacement includes halogen, hydroxyl, and the like. Atwo hydrogen atom replacement includes carbonyl, oximino, and the like.A two hydrogen atom replacement from adjacent carbon atoms includesepoxy, and the like. Three hydrogen replacement includes cyano, and thelike. The term substituted is used throughout the present specificationto indicate that a hydrocarbyl moiety, inter alia, aromatic ring, alkylchain; can have one or more of the hydrogen atoms replaced by asubstituent. When a moiety is described as “substituted” any number ofthe hydrogen atoms may be replaced. For example, 4-hydroxyphenyl is a“substituted aromatic carbocyclic ring (aryl ring)”,(N,N-dimethyl-5-amino)octanyl is a “substituted C₈ linear alkyl unit,3-guanidinopropyl is a “substituted C₃ linear alkyl unit,” and2-carboxypyridinyl is a “substituted heteroaryl unit.”

The following are non-limiting examples of units which can substitutefor hydrogen atoms on a carbocyclic, aryl, heterocyclic, or heteroarylunit:

-   -   i) C₁-C₁₂ linear, branched, or cyclic alkyl, alkenyl, and        alkynyl; methyl (C₁), ethyl (C₂), ethenyl (C₂), ethynyl (C₂),        n-propyl (C₃), iso-propyl (C₃), cyclopropyl (C₃), 3-propenyl        (C₃), 1-propenyl (also 2-methylethenyl) (C₃), isopropenyl (also        2-methylethen-2-yl) (C₃), prop-2-ynyl (also propargyl) (C₃),        propyn-1-yl (C₃), n-butyl (C₄), sec-butyl (C₄), iso-butyl (C₄),        tert-butyl (C₄), cyclobutyl (C₄), buten-4-yl (C₄), cyclopentyl        (C₅), cyclohexyl (C₆);    -   ii) substituted or unsubstituted C₆ or C₁₀ aryl; for example,        phenyl, naphthyl (also referred to herein as naphthylen-1-yl        (C₁₀) or naphthylen-2-yl (C₁₀));    -   iii) substituted or unsubstituted C₆ or C₁₀ alkylenearyl; for        example, benzyl, 2-phenylethyl, naphthylen-2-ylmethyl;    -   iv) substituted or unsubstituted C₁-C₉ heterocyclic rings; as        described herein below;    -   v) substituted or unsubstituted C₁-C₉ heteroaryl rings; as        described herein below;    -   vi) —(CR^(102a)R^(102b))_(a)OR¹⁰¹; for example, —OH, —CH₂OH,        —OCH₃, —CH₂OCH₃, —OCH₂CH₃, —CH₂OCH₂CH₃, —OCH₂CH₂CH₃, and        —CH₂OCH₂CH₂CH₃;    -   vii) —(CR^(102a)R^(102b))_(a)C(O)R¹⁰¹; for example, —COCH₃,        —CH₂COCH₃, —COCH₂CH₃, —CH₂COCH₂CH₃, —COCH₂CH₂CH₃, and        —CH₂COCH₂CH₂CH₃;    -   viii) —(CR^(102a)R^(102b))_(a)C(O)OR¹⁰¹; for example, —CO₂CH₃,        —CH₂CO₂CH₃, —CO₂CH₂CH₃, —CH₂CO₂CH₂CH₃, —CO₂CH₂CH₂CH₃, and        —CH₂CO₂CH₂CH₂CH₃;    -   ix) —(CR^(102a)R^(102b))_(a)C(O)N(R¹⁰¹)₂; for example, —CONH₂,        —CH₂CONH₂, —CONHCH₃, —CH₂CONHCH₃, —CON(CH₃)₂, and —CH₂CON(CH₃)₂;    -   x) —(CR^(102a)R^(102b))_(a)N(R¹⁰¹)₂; for example, —NH₂, —CH₂NH₂,        —NHCH₃, —CH₂NHCH₃, —N(CH₃)₂, and —CH₂N(CH₃)₂;    -   xi) halogen; —F, —Cl, —Br, and —I;    -   xii) —(CR^(102a)R^(102b))_(a)CN;    -   xiii) —(CR^(102a)R^(102b))_(a)NO₂;    -   xiv) —CH_(j)X_(k); wherein X is halogen, the index j is an        integer from 0 to 2, j+k=3; for example, —CH₂F, —CHF₂, —CF₃,        —CCl₃, or —CBr₃;    -   xv) —(CR^(102a)R^(102b))_(a)SR¹⁰¹; —SH, —CH₂SH, —SCH₃, —CH₂SCH₃,        —SC₆H₅, and —CH₂SC₆H₅;    -   xvi) —(CR^(102a)R^(102b))_(a)SO₂R¹⁰¹; for example, —SO₂H,        —CH₂SO₂H, —SO₂CH₃, —CH₂SO₂CH₃, —SO₂C₆H₅, and —CH₂SO₂C₆H₅; and    -   xvii) —(CR^(102a)R^(102b))_(a)SO₃R¹⁰¹; for example, —SO₃H,        —CH₂SO₃H, —SO₃CH₃, —CH₂SO₃CH₃, —SO₃C₆H₅, and —CH₂SO₃C₆H₅;        wherein each R¹⁰¹ is independently hydrogen, substituted or        unsubstituted C₁-C₆ linear, branched, or cyclic alkyl, phenyl,        benzyl, heterocyclic, or heteroaryl; or two R¹⁰¹ units can be        taken together to form a ring comprising 3-7 atoms; R^(102a) and        R^(102b) are each independently hydrogen or C₁-C₄ linear or        branched alkyl; the index “a” is from 0 to 4.

For the purposes of the present disclosure the terms “compound,”“analog,” and “composition of matter” stand equally well for each otherand are used interchangeably throughout the specification. The disclosedcompounds include all enantiomeric forms, diastereomeric forms, salts,and the like.

The compounds disclosed herein include all salt forms, for example,salts of both basic groups, inter alia, amines, as well as salts ofacidic groups, inter alia, carboxylic acids. The following arenon-limiting examples of anions that can form salts with protonatedbasic groups: chloride, bromide, iodide, sulfate, bisulfate, carbonate,bicarbonate, phosphate, formate, acetate, propionate, butyrate,pyruvate, lactate, oxalate, malonate, maleate, succinate, tartrate,fumarate, citrate, and the like. The following are non-limiting examplesof cations that can form salts of acidic groups: ammonium, sodium,lithium, potassium, calcium, magnesium, bismuth, lysine, and the like.

The disclosed compounds have Formula (I):

wherein the carbon atom having the amino unit has the (S)stereochemistry as indicated in the following formula:

The units which comprise R and Z can comprise units having anyconfiguration, and, as such, the disclosed compounds can be singleenantiomers, diastereomeric pairs, or combinations thereof. In addition,the compounds can be isolated as salts or hydrates. In the case ofsalts, the compounds can comprises more than one cation or anion. In thecase of hydrates, any number of water molecules, or fractional partthereof (for example, less than 1 water molecule present for eachmolecule of analog) can be present.R Units

R is a substituted or unsubstituted thiazolyl unit having the formula:

R², R³, and R⁴ are substituent groups that can be independently chosenfrom a wide variety of non-carbon atom containing units (for example,hydrogen, hydroxyl, amino, halogen, nitro, and the like) or organicsubstituent units, such as substituted and unsubstituted acyclichydrocarbyl and cyclic hydrocarbyl units as described herein. The carboncomprising units can comprise from 1 to 12 carbon atoms, or 1 to 10carbon atoms, or 1 to 6 carbon atoms.

An example of compounds of Formula (I) include compounds wherein R unitsare thiazol-2-yl units having the formula:

wherein R² and R³ are each independently chosen from:

-   -   i) hydrogen;    -   ii) substituted or unsubstituted C₁-C₆ linear, branched, or        cyclic alkyl;    -   iii) substituted or unsubstituted C₂-C₆ linear, branched, or        cyclic alkenyl;    -   iv) substituted or unsubstituted C₂-C₆ linear or branched        alkynyl;    -   v) substituted or unsubstituted C₆ or C₁₀ aryl;    -   vi) substituted or unsubstituted C₁-C₉ heteroaryl;    -   vii) substituted or unsubstituted C₁-C₉ heterocyclic; or    -   viii) R² and R³ can be taken together to form a saturated or        unsaturated ring having from 5 to 7 atoms; wherein from 1 to 3        atoms can optionally be heteroatoms chosen from oxygen,        nitrogen, and sulfur.

The following are non-limiting examples of units that can substitute forone or more hydrogen atoms on the R² and R³ units. The followingsubstituents, as well as others not herein described, are eachindependently chosen:

-   -   i) C₁-C₁₂ linear, branched, or cyclic alkyl, alkenyl, and        alkynyl; methyl (C₁), ethyl (C₂), ethenyl (C₂), ethynyl (C₂),        n-propyl (C₃), iso-propyl (C₃), cyclopropyl (C₃), 3-propenyl        (C₃), 1-propenyl (also 2-methylethenyl) (C₃), isopropenyl (also        2-methylethen-2-yl) (C₃), prop-2-ynyl (also propargyl) (C₃),        propyn-1-yl (C₃), n-butyl (C₄), sec-butyl (C₄), iso-butyl (C₄),        tert-butyl (C₄), cyclobutyl (C₄), buten-4-yl (C₄), cyclopentyl        (C₅), cyclohexyl (C₆);    -   ii) substituted or unsubstituted C₆ or C₁₀ aryl; for example,        phenyl, naphthyl (also referred to herein as naphthylen-1-yl        (C₁₀) or naphthylen-2-yl (C₁₀));    -   iii) substituted or unsubstituted C₆ or C₁₀ alkylenearyl; for        example, benzyl, 2-phenylethyl, naphthylen-2-ylmethyl;    -   iv) substituted or unsubstituted C₁-C₉ heterocyclic rings; as        described herein;    -   v) substituted or unsubstituted C₁-C₉ heteroaryl rings; as        described herein;    -   vi) —(CR^(21a)R^(21b))_(p)OR²⁰; for example, —OH, —CH₂OH, —OCH₃,        —CH₂OCH₃, —OCH₂CH₃, —CH₂OCH₂CH₃, —OCH₂CH₂CH₃, and        —CH₂OCH₂CH₂CH₃;    -   vii) —(CR^(21a)R^(21b))_(p)C(O)R²⁰; for example, —COCH₃,        —CH₂COCH₃, —COCH₂CH₃, —CH₂COCH₂CH₃, —COCH₂CH₂CH₃, and        —CH₂COCH₂CH₂CH₃;    -   viii) —(CR^(21a)R^(21b))_(p)C(O)OR²⁰; for example,        —CO₂CH₃,—CH₂CO₂CH₃, —CO₂CH₂CH₃, —CH₂CO₂CH₂CH₃, —CO₂CH₂CH₂CH₃,        and —CH₂CO₂CH₂CH₂CH₃;    -   x) —(CR^(21a)R^(21b))_(p)C(O)N(R²⁰)₂; for example, —CONH₂,        —CH₂CONH₂, —CONHCH₃, —CH₂CONHCH₃, —CON(CH₃)₂, and —CH₂CON(CH₃)₂;    -   x) —(CR^(21a)R^(21b))_(p)N(R²⁰)₂; for example, —NH₂, —CH₂NH₂,        —NHCH₃, —CH₂NHCH₃, —N(CH₃)₂, and —CH₂N(CH₃)₂;    -   xi) halogen; —F, —Cl, —Br, and —I;    -   xii) —(CR^(21a)R^(21b))_(p)CN;    -   xiii) —(CR^(21a)R^(21b))_(p)NO₂;    -   xiv) —(CH_(j′)X_(k′))_(h)CH_(j)X_(k); wherein X is halogen, the        index j is an integer from 0 to 2, j+k=3, the index j′ is an        integer from 0 to 2, j′+k′=2, the index h is from 0 to 6; for        example, —CH₂F, —CHF₂, —CF₃, —CH₂CF₃, —CHFCF₃, —CCl₃, or —CBr₃;    -   xv) —(CR^(21a)R^(21b))_(p)SR²⁰; —SH, —CH₂SH, —SCH₃, —CH₂SCH₃,        —SC₆H₅, and —CH₂SC₆H₅;    -   xvi) —(CR^(21a)R^(21b))_(p)SO₂R²⁰, for example, —SO₂H, —CH₂SO₂H,        —SO₂CH₃, —CH₂SO₂CH₃, —SO₂C₆H₅, and —CH₂SO₂C₆H₅; and    -   xvii) —(CR^(21a)R^(21b))_(p)SO₃R²⁰; for example, —SO₃H,        —CH₂SO₃H, —SO₃CH₃, —CH₂SO₃CH₃, —SO₃C₆H₅, and —CH₂SO₃C₆H₅;        wherein each R²⁰ is independently hydrogen, substituted or        unsubstituted C₁-C₄ linear, branched, or cyclic alkyl, phenyl,        benzyl, heterocyclic, or heteroaryl; or two R²⁰ units can be        taken together to form a ring comprising 3-7 atoms; R^(21a) and        R^(21b) are each independently hydrogen or C₁-C₄ linear or        branched alkyl; the index p is from 0 to 4.

An example of compounds of Formula (I) includes R units having theformula:

wherein R³ is hydrogen and R² is a unit chosen from methyl (C₁), ethyl(C₂), n-propyl (C₃), iso-propyl (C₃), n-butyl (C₄), sec-butyl (C₄),iso-butyl (C₄), tert-butyl (C₄), n-pentyl (C₅), 1-methylbutyl (C₅),2-methylbutyl (C₅), 3-methylbutyl (C₅), cyclopropyl (C₃), n-hexyl (C₆),4-methylpentyl (C₆), and cyclohexyl (C₆).

Another example of compounds of Formula (I) include R units having theformula:

wherein R² is a unit chosen from methyl (C₁), ethyl (C₂), n-propyl (C₃),iso-propyl (C₃), n-butyl (C₄), sec-butyl (C₄), iso-butyl (C₄), andtert-butyl (C₄); and R³ is a unit chosen from methyl (C₁) or ethyl (C₂).Non-limiting examples of this aspect of R includes4,5-dimethylthiazol-2-yl, 4-ethyl-5-methylthiazol-2-yl,4-methyl-5-ethylthiazol-2-yl, and 4,5-diethylthiazol-2-yl.

A further example of compounds of Formula (I) includes R units whereinR³ is hydrogen and R² is a substituted alkyl unit, said substitutionschosen from:

-   -   i) halogen: —F, —Cl, —Br, and —I;    -   ii) —N(R¹¹)₂; and    -   iii) —OR¹¹;        wherein each R¹¹ is independently hydrogen or C₁-C₄ linear or        branched alkyl. Non-limiting examples of units that can be a        substitute for a R² or R³ hydrogen atom on R units include        —CH₂F, —CHF₂, —CF₃, —CH₂CF₃, —CH₂CH₂CF₃, —CH₂Cl, —CH₂OH,        —CH₂OCH₃, —CH₂CH₂OH, —CH₂CH₂OCH₃, —CH₂NH₂, —CH₂NHCH₃,        —CH₂N(CH₃)₂, and —CH₂NH(CH₂CH₃).

Further non-limiting examples of units that can be a substitute for a R²or R³ hydrogen atom on R units include 2,2-difluorocyclopropyl,2-methoxycyclohexyl, and 4-chlorocyclohexyl.

A yet further example of compounds of Formula (I), R units include unitswherein R³ is hydrogen and R² is phenyl or substituted phenyl, whereinnon-limiting examples of R² units include phenyl, 3,4-dimethylphenyl,4-tert-butylphenyl, 4-cyclopropylphenyl, 4-diethylaminophenyl,4-(trifluoromethyl)phenyl, 4-methoxyphenyl, 4-(difluoromethoxy)phenyl,4-(trifluoromethoxy)phenyl, 3-chloropheny, 4-chlorophenyl, and3,4-dichlorophenyl, which when incorporated into the definition of Raffords the following R units 4-phenylthiazol-2-yl,3,4-dimethylphenylthiazol-2-yl, 4-tert-butylphenylthiazol-2-yl,4-cyclopropylphenylthiazol-2-yl, 4-diethylaminophenylthiazol-2-yl,4-(trifluoromethyl)phenylthiazol-2-yl, 4-methoxyphenylthiazol-2-yl,4-(difluoromethoxy)phenylthiazol-2-yl,4-(trifluoromethoxy)phenylthiazol-2-yl, 3-chlorophenylthiazol-2-yl,4-chlorophenylthiazol-2-yl, and 3,4-dichlorophenylthiazol-2-yl.

A still further example of compounds of Formula (I) includes R unitswherein R² is chosen from hydrogen, methyl, ethyl, n-propyl, andiso-propyl and R³ is phenyl or substituted phenyl. A non-limitingexample of a R unit according to the fifth aspect of the first categoryof R units includes 4-methyl-5-phenylthiazol-2-yl and4-ethyl-5-phenylthiazol-2-yl.

Another further example of compounds of Formula (I) includes R unitswherein R³ is hydrogen and R² is a substituted or unsubstitutedheteroaryl unit chosen from 1,2,3,4-tetrazol-1-yl,1,2,3,4-tetrazol-5-yl, [1,2,3]triazol-4-yl, [1,2,3]triazol-5-yl,[1,2,4]triazol-4-yl, [1,2,4]triazol-5-yl, imidazol-2-yl, imidazol-4-yl,pyrrol-2-yl, pyrrol-3-yl, oxazol-2-yl, oxazol-4-yl, oxazol-5-yl,isoxazol-3-yl, isoxazol-4-yl, isoxazol-5-yl, [1,2,4]oxadiazol-3-yl,[1,2,4]oxadiazol-5-yl, [1,3,4]oxadiazol-2-yl, furan-2-yl, furan-3-yl,thiophen-2-yl, thiophen-3-yl, isothiazol-3-yl, isothiazol-4-yl,isothiazol-5-yl, thiazol-2-yl, thiazol-4-yl, thiazol-5-yl,[1,2,4]thiadiazol-3-yl, [1,2,4]thiadiazol-5-yl, and[1,3,4]thiadiazol-2-yl.

Further non-limiting example of compounds of Formula (I) includes Runits wherein R² is substituted or unsubstituted thiophen-2-yl, forexample thiophen-2-yl, 5-chlorothiophen-2-yl, and 5-methylthiophen-2-yl.

A still further example of compounds of Formula (I) includes R unitswherein R² is substituted or unsubstituted thiophen-3-yl, for examplethiophen-3-yl, 5-chlorothiophen-3-yl, and 5-methylthiophen-3-yl.

Another example of compounds of Formula (I) includes R units wherein R²and R³ are taken together to form a saturated or unsaturated ring havingfrom 5 to 7 atoms. Non-limiting examples of the sixth aspect of thefirst category of R units include5,6-dihydro-4H-cyclopenta[d]thiazol-2-yl and4,5,6,7-tetrahydrobenzo[d]thiazol-2-yl.

Further examples of compounds of Formula (I) include R units that arethiazol-4-yl units having the formula:

wherein R⁴ is a unit chosen from:

-   -   i) hydrogen;    -   ii) substituted or unsubstituted C₁-C₆ linear, branched, or        cyclic alkyl;    -   iii) substituted or unsubstituted C₂-C₆ linear, branched, or        cyclic alkenyl;    -   iv) substituted or unsubstituted C₂-C₆ linear or branched        alkynyl;    -   v) substituted or unsubstituted C₆ or C₁₀ aryl;    -   vi) substituted or unsubstituted C₁-C₉ heteroaryl; or    -   vii) substituted or unsubstituted C₁-C₉ heterocyclic.

The following are non-limiting examples of units that can substitute forone or more hydrogen atoms on the R⁴ units. The following substituents,as well as others not herein described, are each independently chosen:

-   -   i) C₁-C₁₂ linear, branched, or cyclic alkyl, alkenyl, and        alkynyl; methyl (C₁), ethyl (C₂), ethenyl (C₂), ethynyl (C₂),        n-propyl (C₃), iso-propyl (C₃), cyclopropyl (C₃), 3-propenyl        (C₃), 1-propenyl (also 2-methylethenyl) (C₃), isopropenyl (also        2-methylethen-2-yl) (C₃), prop-2-ynyl (also propargyl) (C₃),        propyn-1-yl (C₃), n-butyl (C₄), sec-butyl (C₄), iso-butyl (C₄),        tert-butyl (C₄), cyclobutyl (C₄), buten-4-yl (C₄), cyclopentyl        (C₅), cyclohexyl (C₆);    -   ii) substituted or unsubstituted C₆ or C₁₀ aryl; for example,        phenyl, naphthyl (also referred to herein as naphthylen-1-yl        (C₁₀) or naphthylen-2-yl (C₁₀));    -   iii) substituted or unsubstituted C₆ or C₁₀ alkylenearyl; for        example, benzyl, 2-phenylethyl, naphthylen-2-ylmethyl;    -   iv) substituted or unsubstituted C₁-C₉ heterocyclic rings; as        described herein below;    -   v) substituted or unsubstituted C₁-C₉ heteroaryl rings; as        described herein below;    -   vi) —(CR^(21a)R^(21b))_(p)OR²⁰; for example, —OH, —CH₂OH, —OCH₃,        —CH₂OCH₃, —OCH₂CH₃, —CH₂OCH₂CH₃, —OCH₂CH₂CH₃, and        —CH₂OCH₂CH₂CH₃;    -   vii) —(CR^(21a)R^(21b))_(p)C(O)R²⁰; for example, —COCH₃,        —CH₂COCH₃, —COCH₂CH₃, —CH₂COCH₂CH₃, —COCH₂CH₂CH₃, and        —CH₂COCH₂CH₂CH₃;    -   viii) —(CR^(21a)R^(21b))_(p)C(O)OR²⁰; for example, —CO₂CH₃,        —CH₂CO₂CH₃, —CO₂CH₂CH₃, —CH₂CO₂CH₂CH₃, —CO₂CH₂CH₂CH₃, and        —CH₂CO₂CH₂CH₂CH₃;    -   xi) —(CR^(21a)R^(21b))_(p)C(O)N(R²⁰)₂; for example, —CONH₂,        —CH₂CONH₂, —CONHCH₃, —CH₂CONHCH₃, —CON(CH₃)₂, and —CH₂CON(CH₃)₂;    -   x) —(CR^(21a)R^(21b))_(p)N(R²⁰)₂; for example, —NH₂, —CH₂NH₂,        —NHCH₃, —CH₂NHCH₃, —N(CH₃)₂, and —CH₂N(CH₃)₂;    -   xi) halogen; —F, —Cl, —Br, and —I;    -   xii) —(CR^(21a)R^(21b))_(p)CN;    -   xiii) —(CR^(21a)R^(21b))_(p)NO₂;    -   xiv) —(CH_(j′)X_(k′))_(h)CH_(j)X_(k); wherein X is halogen, the        index j is an integer from 0 to 2, j+k=3, the index j′ is an        integer from 0 to 2, j′+k′=2, the index h is from 0 to 6; for        example, —CH₂F, —CHF₂, —CF₃, —CH₂CF₃, —CHFCF₃, —CCl₃, or —CBr₃;    -   xv) —(CR^(21a)R^(21b))_(p)SR²⁰; —SH, —CH₂SH, —SCH₃, —CH₂SCH₃,        —SC₆H₅, and —CH₂SC₆H₅;    -   xvi) —(CR^(21a)R^(21b))_(p)SO₂R²⁰; for example, —SO₂H, —CH₂SO₂H,        —SO₂CH₃, —CH₂SO₂CH₃, —SO₂C₆H₅, and —CH₂SO₂C₆H₅; and    -   xvii) —(CR^(21a)R^(21b))_(p)SO₃R²⁰; for example, —SO₃H,        —CH₂SO₃H, —SO₃CH₃, —CH₂SO₃CH₃, —SO₃C₆H₅, and —CH₂SO₃C₆H₅;        wherein each R²⁰ is independently hydrogen, substituted or        unsubstituted C₁-C₄ linear, branched, or cyclic alkyl, phenyl,        benzyl, heterocyclic, or heteroaryl; or two R²⁰ units can be        taken together to form a ring comprising 3-7 atoms; R^(21a) and        R^(21b) are each independently hydrogen or C₁-C₄ linear or        branched alkyl; the index p is from 0 to 4.

An example of compounds of Formula (I) includes R units wherein R⁴ ishydrogen.

A further example of compounds of Formula (I) includes R units whereinR⁴ is a unit chosen from methyl (C₁), ethyl (C₂), n-propyl (C₃),iso-propyl (C₃), n-butyl (C₄), sec-butyl (C₄), iso-butyl (C₄), andtert-butyl (C₄). Non-limiting examples of this aspect of R includes2-methylthiazol-4-yl, 2-ethylthiazol-4-yl, 2-(n-propyl)thiazol-4-yl, and2-(iso-propyl)thiazol-4-yl.

A still further example of compounds of Formula (I) includes R unitswherein R⁴ is substituted or unsubstituted phenyl, non-limiting examplesof which include phenyl, 2-fluorophenyl, 2-chlorophenyl, 2-methylphenyl,2-methoxyphenyl, 3-fluorophenyl, 3-chlorophenyl, 3-methylphenyl,3-methoxyphenyl, 4-fluorophenyl, 4-chlorophenyl, 4-methylphenyl, and4-methoxyphenyl.

Yet further example of compounds of Formula (I) includes R units whereinR⁴ is substituted or unsubstituted heteroaryl, non-limiting examples ofwhich include thiophen-2-yl, thiophen-3-yl, thiazol-2-yl, thiazol-4-yl,thiazol-5-yl, 2,5-dimethylthiazol-4-yl, 2,4-dimethylthiazol-5-yl,4-ethylthiazol-2-yl, oxazol-2-yl, oxazol-4-yl, oxazol-5-yl, and3-methyl-1,2,4-oxadiazol-5-yl.

Another example of 5-member ring R units includes substituted orunsubstituted imidazolyl units having the formula:

One example of imidazolyl R units includes imidazol-2-yl units havingthe formula:

wherein R² and R³ are each independently chosen from:

-   -   i) hydrogen;    -   ii) substituted or unsubstituted C₁-C₆ linear, branched, or        cyclic alkyl;    -   iii) substituted or unsubstituted C₂-C₆ linear, branched, or        cyclic alkenyl;    -   iv) substituted or unsubstituted C₂-C₆ linear or branched        alkynyl;    -   v) substituted or unsubstituted C₆ or C₁₀ aryl;    -   vi) substituted or unsubstituted C₁-C₉ heteroaryl;    -   vii) substituted or unsubstituted C₁-C₉ heterocyclic; or    -   viii) R² and R³ can be taken together to form a saturated or        unsaturated ring having from 5 to 7 atoms; wherein from 1 to 3        atoms can optionally be heteroatoms chosen from oxygen,        nitrogen, and sulfur.

The following are non-limiting examples of units that can substitute forone or more hydrogen atoms on the R² and R³ units. The followingsubstituents, as well as others not herein described, are eachindependently chosen:

-   -   i) C₁-C₁₂ linear, branched, or cyclic alkyl, alkenyl, and        alkynyl; methyl (C₁), ethyl (C₂), ethenyl (C₂), ethynyl (C₂),        n-propyl (C₃), iso-propyl (C₃), cyclopropyl (C₃), 3-propenyl        (C₃), 1-propenyl (also 2-methylethenyl) (C₃), isopropenyl (also        2-methylethen-2-yl) (C₃), prop-2-ynyl (also propargyl) (C₃),        propyn-1-yl (C₃), n-butyl (C₄), sec-butyl (C₄), iso-butyl (C₄),        tert-butyl (C₄), cyclobutyl (C₄), buten-4-yl (C₄), cyclopentyl        (C₅), cyclohexyl (C₆);    -   ii) substituted or unsubstituted C₆ or C₁₀ aryl; for example,        phenyl, naphthyl (also referred to herein as naphthylen-1-yl        (C₁₀) or naphthylen-2-yl (C₁₀));    -   iii) substituted or unsubstituted C₆ or C₁₀ alkylenearyl; for        example, benzyl, 2-phenylethyl, naphthylen-2-ylmethyl;    -   iv) substituted or unsubstituted C₁-C₉ heterocyclic rings; as        described herein;    -   v) substituted or unsubstituted C₁-C₉ heteroaryl rings; as        described herein;    -   vi) —(CR^(21a)R^(21b))_(z)OR²⁰; for example, —OH, —CH₂OH, —OCH₃,        —CH₂OCH₃, —OCH₂CH₃, —CH₂OCH₂CH₃, —OCH₂CH₂CH₃, and        —CH₂OCH₂CH₂CH₃;    -   vii) —(CR^(21a)R^(21b))_(z)C(O)R²⁰; for example, —COCH₃,        —CH₂COCH₃, —COCH₂CH₃, —CH₂COCH₂CH₃, —COCH₂CH₂CH₃, and        —CH₂COCH₂CH₂CH₃;    -   viii) —(CR^(21a)R^(21b))_(z)C(O)OR²⁰; for example, —CO₂CH₃,        —CH₂CO₂CH₃, —CO₂CH₂CH₃, —CH₂CO₂CH₂CH₃, —CO₂CH₂CH₂CH₃, and        —CH₂CO₂CH₂CH₂CH₃;    -   xii) —(CR^(21a)R^(21b))_(z)C(O)N(R²⁰)₂; for example, —CONH₂,        —CH₂CONH₂, —CONHCH₃, —CH₂CONHCH₃, —CON(CH₃)₂, and —CH₂CON(CH₃)₂;    -   x) —(CR^(21a)R^(21b))_(z)N(R²⁰)₂; for example, —NH₂, —CH₂NH₂,        —NHCH₃, —CH₂NHCH₃, —N(CH₃)₂, and —CH₂N(CH₃)₂;    -   xi) halogen; —F, —Cl, —Br, and —I;    -   xii) —(CR^(21a)R^(21b))_(z)CN;    -   xiii) —(CR^(21a)R^(21b))_(z)NO₂;    -   xiv) —(CH_(j′)X_(k′))_(h)CH_(j)X_(k); wherein X is halogen, the        index j is an integer from 0 to 2, j+k=3, the index j′ is an        integer from 0 to 2, j′+k′=2, the index h is from 0 to 6; for        example, —CH₂F, —CHF₂, —CF₃, —CH₂CF₃, —CHFCF₃, —CCl₃, or —CBr₃;    -   xv) —(CR^(21a)R^(21b))_(z)SR²⁰; —SH, —CH₂SH, —SCH₃, —CH₂SCH₃,        —SC₆H₅, and —CH₂SC₆H₅;    -   xvi) —(CR^(21a)R^(21b))_(z)SO₂R²⁰; for example, —SO₂H, —CH₂SO₂H,        —SO₂CH₃, —CH₂SO₂CH₃, —SO₂C₆H₅, and —CH₂SO₂C₆H₅; and    -   xvii) —(CR^(21a)R^(21b))_(z)SO₃R²⁰; for example, —SO₃H,        —CH₂SO₃H, —SO₃CH₃, —CH₂SO₃CH₃, —SO₃C₆H₅, and —CH₂SO₃C₆H₅;        wherein each R²⁰ is independently hydrogen, substituted or        unsubstituted C₁-C₄ linear, branched, or cyclic alkyl, phenyl,        benzyl, heterocyclic, or heteroaryl; or two R²⁰ units can be        taken together to form a ring comprising 3-7 atoms; R^(21a) and        R^(21b) are each independently hydrogen or C₁-C₄ linear or        branched alkyl; the index p is from 0 to 4.

One example of R units includes compounds wherein R units have theformula:

wherein R³ is hydrogen and R² is a unit chosen from methyl (C₁), ethyl(C₂), n-propyl (C₃), iso-propyl (C₃), n-butyl (C₄), sec-butyl (C₄),iso-butyl (C₄), and tert-butyl (C₄).

Another example of R units includes compounds wherein R² is a unitchosen from methyl (C₁), ethyl (C₂), n-propyl (C₃), iso-propyl (C₃),n-butyl (C₄), sec-butyl (C₄), iso-butyl (C₄), and tert-butyl (C₄); andR³ is a unit chosen from methyl (C₁) or ethyl (C₂). Non-limitingexamples of this aspect of R includes 4,5-dimethylimidazol-2-yl,4-ethyl-5-methylimidazol-2-yl, 4-methyl-5-ethylimidazol-2-yl, and4,5-diethylimidazol-2-yl.

An example of R units includes compounds wherein R³ is hydrogen and R²is a substituted alkyl unit chosen, said substitutions chosen from:

-   -   i) halogen: —F, —Cl, —Br, and —I;    -   ii) —N(R¹¹)₂; and    -   iii) —OR¹¹;        wherein each R¹¹ is independently hydrogen or C₁-C₄ linear or        branched alkyl.

Non-limiting examples of units comprising this embodiment of R includes:—CH₂F, —CHF₂, —CF₃, —CH₂CF₃, —CH₂Cl, —CH₂OH, —CH₂OCH₃, —CH₂CH₂OH,—CH₂CH₂OCH₃, —CH₂NH₂, —CH₂NHCH₃, —CH₂N(CH₃)₂, and —CH₂NH(CH₂CH₃).

A yet further example of R units include units wherein R³ is hydrogenand R² is phenyl.

A still further example of R units include units wherein R³ is hydrogenand R² is a heteroaryl unit chosen from 1,2,3,4-tetrazol-1-yl,1,2,3,4-tetrazol-5-yl, [1,2,3]triazol-4-yl, [1,2,3]triazol-5-yl,[1,2,4]triazol-4-yl, [1,2,4]triazol-5-yl, imidazol-2-yl, imidazol-4-yl,pyrrol-2-yl, pyrrol-3-yl, oxazol-2-yl, oxazol-4-yl, oxazol-5-yl,isoxazol-3-yl, isoxazol-4-yl, isoxazol-5-yl, [1,2,4]oxadiazol-3-yl,[1,2,4]oxadiazol-5-yl, [1,3,4]oxadiazol-2-yl, furan-2-yl, furan-3-yl,thiophen-2-yl, thiophen-3-yl, isothiazol-3-yl, isothiazol-4-yl,isothiazol-5-yl, thiazol-2-yl, thiazol-4-yl, thiazol-5-yl,[1,2,4]thiadiazol-3-yl, [1,2,4]thiadiazol-5-yl, and[1,3,4]thiadiazol-2-yl.Z Units

Z is a unit having the formula:-(L)_(n)-R¹

-   -   R¹ is chosen from:    -   i) hydrogen;    -   ii) hydroxyl;    -   iii) amino;    -   iv) substituted or unsubstituted C₁-C₆ linear, branched or        cyclic alkyl;    -   v) substituted or unsubstituted C₁-C₆ linear, branched or cyclic        alkoxy;    -   vi) substituted or unsubstituted C₆ or C₁₀ aryl;    -   vii) substituted or unsubstituted C₁-C₉ heterocyclic rings; or    -   viii) substituted or unsubstituted C₁-C₉ heteroaryl rings.

The following are non-limiting examples of units that can substitute forone or more hydrogen atoms on the R¹ units. The following substituents,as well as others not herein described, are each independently chosen:

-   -   i) C₁-C₁₂ linear, branched, or cyclic alkyl, alkenyl, and        alkynyl; methyl (C₁), ethyl (C₂), ethenyl (C₂), ethynyl (C₂),        n-propyl (C₃), iso-propyl (C₃), cyclopropyl (C₃), 3-propenyl        (C₃), 1-propenyl (also 2-methylethenyl) (C₃), isopropenyl (also        2-methylethen-2-yl) (C₃), prop-2-ynyl (also propargyl) (C₃),        propyn-1-yl (C₃), n-butyl (C₄), sec-butyl (C₄), iso-butyl (C₄),        tert-butyl (C₄), cyclobutyl (C₄), buten-4-yl (C₄), cyclopentyl        (C₅), cyclohexyl (C₆);    -   ii) substituted or unsubstituted C₆ or C₁₀ aryl; for example,        phenyl, naphthyl (also referred to herein as naphthylen-1-yl        (C₁₀) or naphthylen-2-yl (C₁₀));    -   iii) substituted or unsubstituted C₆ or C₁₀ alkylenearyl; for        example, benzyl, 2-phenylethyl, naphthylen-2-ylmethyl;    -   iv) substituted or unsubstituted C₁-C₉ heterocyclic rings; as        described herein;    -   v) substituted or unsubstituted C₁-C₉ heteroaryl rings; as        described herein;    -   vi) —(CR^(31a)R^(31b))_(q)OR³⁰; for example, —OH, —CH₂OH, —OCH₃,        —CH₂OCH₃, —OCH₂CH₃, —CH₂OCH₂CH₃, —OCH₂CH₂CH₃, and        —CH₂OCH₂CH₂CH₃;    -   vii) —(CR^(31a)R^(31b))_(q)C(O)R³⁰; for example, —COCH₃,        —CH₂COCH₃, —COCH₂CH₃, —CH₂COCH₂CH₃, —COCH₂CH₂CH₃, and        —CH₂COCH₂CH₂CH₃;    -   viii) —(CR^(31a)R^(31b))_(q)C(O)OR³⁰; for example, —CO₂CH₃,        —CH₂CO₂CH₃, —CO₂CH₂CH₃, —CH₂CO₂CH₂CH₃, —CO₂CH₂CH₂CH₃, and        —CH₂CO₂CH₂CH₂CH₃;    -   xiii) —(CR^(31a)R^(31b))_(q)C(O)N(R³⁰)₂; for example, —CONH₂,        —CH₂CONH₂, —CONHCH₃, —CH₂CONHCH₃, —CON(CH₃)₂, and —CH₂CON(CH₃)₂;    -   x) —(CR^(31a)R^(31b))_(q)N(R³⁰)₂; for example, —NH₂, —CH₂NH₂,        —NHCH₃, —CH₂NHCH₃, —N(CH₃)₂, and —CH₂N(CH₃)₂;    -   xi) halogen; —F, —Cl, —Br, and —I;    -   xii) —(CR^(31a)R^(31b))_(q)CN;    -   xiii) —(CR^(31a)R^(31b))_(q)NO₂;    -   xiv) —(CH_(j′)X_(k′))_(h)CH_(j)X_(k); wherein X is halogen, the        index j is an integer from 0 to 2, j+k=3, the index j′ is an        integer from 0 to 2, j′+k′=2, the index h is from 0 to 6; for        example, —CH₂F, —CHF₂, —CF₃, —CH₂CF₃, —CHFCF₃, —CCl₃, or —CBr₃;    -   xv) —(CR^(31a)R^(31b))_(q)SR³⁰; —SH, —CH₂SH, —SCH₃, —CH₂SCH₃,        —SC₆H₅, and —CH₂SC₆H₅;    -   xvi) —(CR^(31a)R^(31b))_(q)SO₂R³⁰; for example, —SO₂H, —CH₂SO₂H,        —SO₂CH₃, —CH₂SO₂CH₃, —SO₂C₆H₅, and —CH₂SO₂C₆H₅; and    -   xvii) —(CR^(31a)R^(31b))_(q)SO₃R³⁰; for example, —SO₃H,        —CH₂SO₃H, —SO₃CH₃, —CH₂SO₃CH₃, —SO₃C₆H₅, and —CH₂SO₃C₆H₅;        wherein each R³⁰ is independently hydrogen, substituted or        unsubstituted C₁-C₆ linear, branched, or cyclic alkyl, phenyl,        benzyl, heterocyclic, or heteroaryl; or two R³⁰ units can be        taken together to form a ring comprising 3-7 atoms; R^(31a) and        R^(31b) are each independently hydrogen or C₁-C₄ linear or        branched alkyl; the index q is from 0 to 4.

One example of R¹ units includes substituted or unsubstituted phenyl (C₆aryl) units, wherein each substitution is independently chosen from:halogen, C₁-C₄ linear, branched alkyl, or cyclic alkyl, —OR¹¹, —CN,—N(R¹¹)₂, —CO₂R¹¹, —C(O)N(R¹¹)₂, —NR¹¹C(O)R¹¹, —NO₂, and —SO₂R¹¹; eachR¹¹ is independently hydrogen; substituted or unsubstituted C₁-C₄linear, branched, cyclic alkyl, alkenyl, or alkynyl; substituted orunsubstituted phenyl or benzyl; or two R¹¹ units can be taken togetherto form a ring comprising from 3-7 atoms.

Another example of R¹ units includes substituted C₆ aryl units chosenfrom phenyl, 2-fluorophenyl, 3-fluorophenyl, 4-fluorophenyl,2,3-difluorophenyl, 3,4-difluorophenyl, 3,5-difluorophenyl,2-chlorophenyl, 3-chlorophenyl, 4-chlorophenyl, 2,3-dichlorophenyl,3,4-dichlorophenyl, 3,5-dichlorophenyl, 2-hydroxyphenyl,3-hydroxyphenyl, 4-hydroxyphenyl, 2-methoxyphenyl, 3-methoxyphenyl,4-methoxyphenyl, 2,3-dimethoxyphenyl, 3,4-dimethoxyphenyl, and3,5-dimethoxyphenyl.

A further example of R¹ units includes substituted or unsubstituted C₆aryl units chosen from 2,4-difluorophenyl, 2,5-difluorophenyl,2,6-difluorophenyl, 2,3,4-trifluorophenyl, 2,3,5-trifluorophenyl,2,3,6-trifluorophenyl, 2,4,5-trifluorophenyl, 2,4,6-trifluorophenyl,2,4-dichlorophenyl, 2,5-dichlorophenyl, 2,6-dichlorophenyl,3,4-dichlorophenyl, 2,3,4-trichlorophenyl, 2,3,5-trichlorophenyl,2,3,6-trichlorophenyl, 2,4,5-trichlorophenyl, 3,4,5-trichlorophenyl, and2,4,6-trichlorophenyl.

A yet further example of R¹ units includes substituted C₆ aryl unitschosen from 2-methylphenyl, 3-methylphenyl, 4-methylphenyl,2,3-dimethylphenyl, 2,4-dimethylphenyl, 2,5-dimethylphenyl,2,6-dimethylphenyl, 3,4-dimethylphenyl, 2,3,4-trimethylphenyl,2,3,5-trimethylphenyl, 2,3,6-trimethylphenyl, 2,4,5-trimethylphenyl,2,4,6-trimethylphenyl, 2-ethylphenyl, 3-ethylphenyl, 4-ethylphenyl,2,3-diethylphenyl, 2,4-diethylphenyl, 2,5-diethylphenyl,2,6-diethylphenyl, 3,4-diethylphenyl, 2,3,4-triethylphenyl,2,3,5-triethylphenyl, 2,3,6-triethylphenyl, 2,4,5-triethylphenyl,2,4,6-triethylphenyl, 2-isopropylphenyl, 3-isopropylphenyl, and4-isopropylphenyl.

Another still further example of R¹ units includes substituted C₆ arylunits chosen from 2-aminophenyl, 2-(N-methylamino)phenyl,2-(N,N-dimethylamino)phenyl, 2-(N-ethylamino)phenyl,2-(N,N-diethylamino)phenyl, 3-aminophenyl, 3-(N-methylamino)phenyl,3-(N,N-dimethylamino)phenyl, 3-(N-ethylamino)phenyl,3-(N,N-diethylamino)phenyl, 4-aminophenyl, 4-(N-methylamino)phenyl,4-(N,N-dimethylamino)phenyl, 4-(N-ethylamino)phenyl, and4-(N,N-diethylamino)phenyl.

R¹ can comprise heteroaryl units. Non-limiting examples of heteroarylunits include:

R¹ heteroaryl units can be substituted or unsubstituted. Non-limitingexamples of units that can substitute for hydrogen include units chosenfrom:

-   -   i) C₁-C₆ linear, branched, and cyclic alkyl;    -   ii) substituted or unsubstituted phenyl and benzyl;    -   iii) substituted of unsubstituted C₁-C₉ heteroaryl;    -   iv) —C(O)R⁹; and    -   v) —NHC(O)R⁹;        wherein R⁹ is C₁-C₆ linear and branched alkyl; C₁-C₆ linear and        branched alkoxy; or —NHCH₂C(O)R¹⁰; R¹⁰ is chosen from hydrogen,        methyl, ethyl, and tert-butyl.

An example of R¹ relates to units substituted by an alkyl unit chosenfrom methyl, ethyl, n-propyl, iso-propyl, n-butyl, iso-butyl, sec-butyl,and tert-butyl.

Another example of R¹ includes units that are substituted by substitutedor unsubstituted phenyl and benzyl, wherein the phenyl and benzylsubstitutions are chosen from one or more:

-   -   i) halogen;    -   ii) C₁-C₃ alkyl;    -   iii) C₁-C₃ alkoxy;    -   iv) —CO₂R¹¹; and    -   v) —NHCOR¹⁶;        wherein R¹¹ and R¹⁶ are each independently hydrogen, methyl, or        ethyl.

Another example of R¹ relates to phenyl and benzyl units substituted bya carboxy unit having the formula —C(O)R⁹; R⁹ is chosen from methyl,methoxy, ethyl, and ethoxy.

A further example of R¹ includes phenyl and benzyl units substituted byan amide unit having the formula —NHC(O)R⁹; R⁹ is chosen from methyl,methoxy, ethyl, ethoxy, tert-butyl, and tert-butoxy.

A yet further example of R¹ includes phenyl and benzyl units substitutedby one or more fluoro or chloro units.

L Units

L is a linking unit which is present when the index n is equal to 1, butis absent when the index n is equal to 0. L units have the formula:-[Q]_(y)[C(R^(5a)R^(5b))]_(x)[Q¹]_(z)[C(R^(6a)R^(6b))]_(w)—wherein Q and Q¹ are each independently:

-   -   i) —C(O)—;    -   ii) —NH—;    -   iii) —C(O)NH—;    -   iv) —NHC(O)—;    -   v) —NHC(O)NH—;    -   vi) —NHC(O)O—;    -   vii) —C(O)O—;    -   viii) —C(O)NHC(O)—;    -   ix) —O—;    -   x) —S—;    -   xi) —SO₂—;    -   xii) —C(═NH)—;    -   xiii) —C(═NH)NH—;    -   xiv) —NHC(═NH)—; or    -   xv) —NHC(═NH)NH—.        When the index y is equal to 1, Q is present. When the index y        is equal to 0, Q is absent.        When the index z is equal to 1, Q¹ is present. When the index z        is equal to 0, Q¹ is absent.

R^(5a) and R^(5b) are each independently:

-   -   i) hydrogen;    -   ii) hydroxy;    -   iii) halogen;    -   iv) C₁-C₆ substituted or unsubstituted linear or branched alkyl;        or    -   v) a unit having the formula:        —[C(R^(7a)R^(7b))]_(t)R⁸        wherein R^(7a) and R^(7b) are each independently:    -   i) hydrogen; or    -   ii) substituted or unsubstituted C₁-C₆ linear, branched, or        cyclic alkyl.        R⁸ is:    -   i) hydrogen;    -   ii) substituted or unsubstituted C₁-C₆ linear, branched, or        cyclic alkyl;    -   iii) substituted or unsubstituted C₆ or C₁₀ aryl;    -   iv) substituted or unsubstituted C₁-C₉ heteroaryl; or    -   v) substituted or unsubstituted C₁-C₉ heterocyclic.        R^(6a) and R^(6b) are each independently:    -   i) hydrogen; or    -   ii) C₁-C₄ linear or branched alkyl.        The indices t, w and x are each independently from 0 to 4.

The following are non-limiting examples of units that can substitute forone or more hydrogen atoms on R^(5a), R^(5b), R^(7a), R^(7b), and R⁸units. The following substituents, as well as others not hereindescribed, are each independently chosen:

-   -   i) C₁-C₁₂ linear, branched, or cyclic alkyl, alkenyl, and        alkynyl; methyl (C₁), ethyl (C₂), ethenyl (C₂), ethynyl (C₂),        n-propyl (C₃), iso-propyl (C₃), cyclopropyl (C₃), 3-propenyl        (C₃), 1-propenyl (also 2-methylethenyl) (C₃), isopropenyl (also        2-methylethen-2-yl) (C₃), prop-2-ynyl (also propargyl) (C₃),        propyn-1-yl (C₃), n-butyl (C₄), sec-butyl (C₄), iso-butyl (C₄),        tert-butyl (C₄), cyclobutyl (C₄), buten-4-yl (C₄), cyclopentyl        (C₅), cyclohexyl (C₆);    -   ii) substituted or unsubstituted C₆ or C₁₀ aryl; for example,        phenyl, naphthyl (also referred to herein as naphthylen-1-yl        (C₁₀) or naphthylen-2-yl (C₁₀));    -   iii) substituted or unsubstituted C₆ or C₁₀ alkylenearyl; for        example, benzyl, 2-phenylethyl, naphthylen-2-ylmethyl;    -   iv) substituted or unsubstituted C₁-C₉ heterocyclic rings; as        described herein below;    -   v) substituted or unsubstituted C₁-C₉ heteroaryl rings; as        described herein below;    -   vi) —(CR^(41a)R^(41b))_(r)OR⁴⁰; for example, —OH, —CH₂OH, —OCH₃,        —CH₂OCH₃, —OCH₂CH₃, —CH₂OCH₂CH₃, —OCH₂CH₂CH₃, and        —CH₂OCH₂CH₂CH₃;    -   vii) —(CR^(41a)R^(41b))_(r)C(O)R⁴⁰; for example, —COCH₃,        —CH₂COCH₃, —COCH₂CH₃, —CH₂COCH₂CH₃, —COCH₂CH₂CH₃, and        —CH₂COCH₂CH₂CH₃;    -   viii) —(CR^(41a)R^(41b))_(r)C(O)OR⁴⁰; for example, —CO₂CH₃,        —CH₂CO₂CH₃, —CO₂CH₂CH₃, —CH₂CO₂CH₂CH₃, —CO₂CH₂CH₂CH₃, and        —CH₂CO₂CH₂CH₂CH₃;    -   xiv) —(CR^(41a)R^(41b))_(r)C(O)N(R⁴⁰)₂; for example, —CONH₂,        —CH₂CONH₂, —CONHCH₃, —CH₂CONHCH₃, —CON(CH₃)₂, and —CH₂CON(CH₃)₂;    -   x) —(CR^(41a)R^(41b))_(r)N(R⁴⁰)₂; for example, —NH₂, —CH₂NH₂,        —NHCH₃, —CH₂NHCH₃, —N(CH₃)₂, and —CH₂N(CH₃)₂;    -   xi) halogen; —F, —Cl, —Br, and —I;    -   xii) —(CR^(41a)R^(41b))_(r)CN;    -   xiii) —(CR^(41a)R^(41b))_(r)NO₂;    -   xiv) —(CH_(j′)X_(k′))_(h)CH_(j)X_(k); wherein X is halogen, the        index j is an integer from 0 to 2, j+k=3, the index j′ is an        integer from 0 to 2, j′+k′=2, the index h is from 0 to 6; for        example, —CH₂F, —CHF₂, —CF₃, —CH₂CF₃, —CHFCF₃, —CCl₃, or —CBr₃;    -   xv) —(CR^(41a)R^(41b))_(r)SR⁴⁰; —SH, —CH₂SH, —SCH₃, —CH₂SCH₃,        —SC₆H₅, and —CH₂SC₆H₅;    -   xvi) —(CR^(41a)R^(41b))_(r)SO₂R⁴⁰; for example, —SO₂H, —CH₂SO₂H,        —SO₂CH₃, —CH₂SO₂CH₃, —SO₂C₆H₅, and —CH₂SO₂C₆H₅; and    -   xvii) —(CR^(41a)R^(41b))^(r)SO₃R⁴⁰; for example, —SO₃H,        —CH₂SO₃H, —SO₃CH₃, —CH₂SO₃CH₃, —SO₃C₆H₅, and —CH₂SO₃C₆H₅;        wherein each R⁴⁰ is independently hydrogen, substituted or        unsubstituted C₁-C₆ linear, branched, or cyclic alkyl, phenyl,        benzyl, heterocyclic, or heteroaryl; or two R⁴⁰ units can be        taken together to form a ring comprising 3-7 atoms; R^(41a) and        R^(41b) are each independently hydrogen or C₁-C₄ linear or        branched alkyl; the index r is from 0 to 4.

One aspect of L units relates to units having the formula:—C(O)[C(R^(5a)R^(5b))]_(x)NHC(O)—wherein R^(5a) is hydrogen, substituted or unsubstituted C₁-C₄ alkyl,substituted or unsubstituted phenyl, and substituted or unsubstitutedheteroaryl; and the index x is 1 or 2. One embodiment relates to linkingunits having the formula:—C(O)[C(R^(5a)H)]NHC(O)O—;  i)—C(O)[C(R^(5a)H)][CH₂]NHC(O)O—;  ii)—C(O)[CH₂][C(R^(5a)H)]NHC(O)O—;  ii)—C(O)[C(R^(5a)H)]NHC(O)—;  iv)—C(O)[C(R^(5a)H)][CH₂]NHC(O)—;or  v)—C(O)[CH₂][C(R^(5a)H)]NHC(O)—;  vi)

wherein R^(5a) is:

-   -   i) hydrogen;    -   ii) methyl;    -   iii) ethyl;    -   iv) isopropyl;    -   v) phenyl;    -   vi) benzyl;    -   vii) 4-hydroxybenzyl;    -   viii) hydroxymethyl; or    -   ix) 1-hydroxyethyl.        When the index x is equal to 1, this embodiment provides the        following non-limiting examples of L units:

When the index x is equal to 2, this embodiment provides the followingnon-limiting examples of L units:

Another embodiment of L units includes units wherein Q is —C(O)—, theindices x and z are equal to 0, w is equal to 1 or 2, a first R^(6a)unit chosen from phenyl, 2-fluorophenyl, 3-fluorophenyl, 4-fluorophenyl,2,3-difluorophenyl, 3,4-difluorophenyl, 3,5-difluorophenyl,2-chlorophenyl, 3-chlorophenyl, 4-chlorophenyl, 2,3-dichlorophenyl,3,4-dichlorophenyl, 3,5-dichlorophenyl, 2-hydroxyphenyl,3-hydroxyphenyl, 4-hydroxyphenyl, 2-methoxyphenyl, 3-methoxyphenyl,4-methoxyphenyl, 2,3-dimethoxyphenyl, 3,4-dimethoxyphenyl, and3,5-dimethoxyphenyl; a second R^(6a) unit is hydrogen and R^(6b) unitsare hydrogen. For example a linking unit having the formula:

A further example of this embodiment of L includes a first R^(6a) unitas depicted herein above that is a substituted or unsubstitutedheteroaryl unit as described herein above.

A yet further example of this embodiment of L includes units having theformula:—C(O)[C(R^(6a)R^(6b))]_(w)—;wherein R^(6a) and R^(6b) are hydrogen and the index w is equal to 1 or2; said units chosen from:

-   -   i) —C(O)CH₂—; and    -   ii) —C(O)CH₂CH₂—.

Another embodiment of L units includes units having the formula:—C(O)[C(R^(5a)R^(5b))]_(x)C(O)—;wherein R^(5a) and R^(5b) are hydrogen and the index x is equal to 1 or2; said units chosen from:

-   -   i) —C(O)CH₂C(O)—; and    -   ii) —C(O)CH₂CH₂C(O)—.

A still further embodiment of L units includes units having the formula:—C(O)NH[C(R^(5a)R^(5b))]_(x)—;wherein R^(5a) and R^(5b) are hydrogen and the index w is equal to 0, 1or 2; said units chosen from:

-   -   ii) —C(O)NH—;    -   ii) —C(O)NHCH₂—; and    -   iii) —C(O)NHCH₂CH₂—.

A yet still further example of L units includes units having theformula:—SO₂[C(R^(6a)R^(6b))]_(w)—;wherein R^(8a) and R^(8b) are hydrogen or methyl and the index w isequal to 0, 1 or 2; said units chosen from:

-   -   i) —SO₂—;    -   ii) —SO₂CH₂—; and    -   iii) —SO₂CH₂CH₂—.        Tie-2 Signal Amplifiers

The disclosed compounds (analogs) are arranged into several Categoriesto assist the formulator in applying a rational synthetic strategy forthe preparation of analogs which are not expressly exampled herein. Thearrangement into categories does not imply increased or decreasedefficacy for any of the compositions of matter described herein.

A described herein above the disclosed compounds include allpharmaceutically acceptable salt forms. A compound having the formula:

can form salts, for example, a salt of the sulfamic acid:

The compounds can also exist in a zwitterionic form, for example:

oras a salt of a strong acid, for example:

The first aspect of Category I of the present disclosure relates tocompounds wherein R is a substituted or unsubstituted thiazol-2-yl unithaving the formula:

one embodiment of which relates to inhibitors having the formula:

wherein R units are thiazol-2-yl units, that when substituted, aresubstituted with R² and R³ units. R and R^(5a) units are furtherdescribed in Table I.

TABLE I No. R R^(5a) A1 thiazol-2-yl (S)-benzyl A2 4-methylthiazol-2-yl(S)-benzyl A3 4-ethylthiazol-2-yl (S)-benzyl A4 4-propylthiazol-2-yl(S)-benzyl A5 4-iso-propylthiazol-2-yl (S)-benzyl A64-cyclopropylthiazol-2-yl (S)-benzyl A7 4-butylthiazol-2-yl (S)-benzylA8 4-tert-butylthiazol-2-yl (S)-benzyl A9 4-cyclohexylthiazol-2-yl(S)-benzyl A10 4-(2,2,2-trifluoroethyl)thiazol-2-yl (S)-benzyl A114-(3,3,3-trifluoropropyl)thiazol-2-yl (S)-benzyl A124-(2,2-difluorocyclopropyl)thiazol-2-yl (S)-benzyl A134-(methoxymethyl)thiazol-2-yl (S)-benzyl A14 4-(carboxylic acid ethylester)thiazol-2-yl (S)-benzyl A15 4,5-dimethylthiazol-2-yl (S)-benzylA16 4-methyl-5-ethylthiazol-2-yl (S)-benzyl A17 4-phenylthiazol-2-yl(S)-benzyl A18 4-(4-chlorophenyl)thiazol-2-yl (S)-benzyl A194-(3,4-dimethylphenyl)thiazol-2-yl (S)-benzyl A204-methyl-5-phenylthiazol-2-yl (S)-benzyl A214-(thiophen-2-yl)thiazol-2-yl (S)-benzyl A224-(thiophen-3-yl)thiazol-2-yl (S)-benzyl A234-(5-chlorothiophen-2-yl)thiazol-2-yl (S)-benzyl A245,6-dihydro-4H-cyclopenta[d]thiazol-2-yl (S)-benzyl A254,5,6,7-tetrahydrobenzo[d]thiazol-2-yl (S)-benzyl

The compounds encompassed within the first aspect of Category I of thepresent disclosure can be prepared by the procedure outlined in Scheme Iand described in Example 1 herein below.

EXAMPLE 14-{(S)-2-[(S)-2-(tert-Butoxycarbonylamino)-3-phenylpropanamido]-2-(4-ethylthiazol-2-yl)ethyl}phenylsulfamicacid (5)

Preparation of [1-(S)-carbamoyl-2-(4-nitrophenyl)ethyl-carbamic acidtert-butyl ester (1): To a 0° C. solution of2-(S)-tert-butoxycarbonylamino-3-(4-nitrophenyl)-propionic acid andN-methylmorpholine (1.1 mL, 9.65 mmol) in DMF (10 mL) is added dropwiseiso-butyl chloroformate (1.25 mL, 9.65 mmol). The mixture is stirred at0° C. for 20 minutes after which NH₃ (g) is passed through the reactionmixture for 30 minutes at 0° C. The reaction mixture is concentrated andthe residue dissolved in EtOAc, washed successively with 5% citric acid,water, 5% NaHCO₃, water and brine, dried (Na₂SO₄), filtered andconcentrated in vacuo to a residue that is triturated with a mixture ofEtOAc/petroleum ether to provide 2.2 g (74%) of the desired product as awhite solid.

Preparation of [2-(4-nitrophenyl)-1-(S)-thiocarbamoylethyl]carbamic acidtert-butyl ester (2): To a solution of[1-(S)-carbamoyl-2-(4-nitrophenyl)ethyl-carbamic acid tert-butyl ester,1, (0.400 g, 1.29 mmol) in THF (10 mL) is added Lawesson's reagent(0.262 g. 0.65 mmol). The reaction mixture is stirred for 3 hours andconcentrated to a residue which is purified over silica to provide 0.350g (83%) of the desired product. ¹H NMR (300 MHz, CDCl₃) δ 8.29 (s, 1H),8.10 (d. J=8.4 Hz, 2H), 8.01 (s, 1H), 7.42 (d, J=8.4 Hz, 2H), 5.70 (d,J=7.2 Hz, 1H), 4.85 (d, J=7.2 Hz, 1H), 3.11-3.30 (m, 1H), 1.21 (s, 9H).

Preparation of 1-(S)-(4-ethylthiazol-2-yl)-2-(4-nitrophenyl)ethyl amine(3): A mixture of [2-(4-nitrophenyl)-1-(S)-thiocarbamoylethyl]-carbamicacid tert-butyl ester, 2, (0.245 g, 0.753 mmol), 1-bromo-2-butanone(0.125 g, 0.828 mmol) in CH₃CN (5 mL) is refluxed 3 hours. The reactionmixture is cooled to room temperature and diethyl ether is added to thesolution and the precipitate which forms is removed by filtration. Thesolid is dried under vacuum to afford 0.242 g (90% yield) of the desiredproduct. ESI+ MS 278 (M+1).

Preparation of{1-[1-(4-ethylthiazol-2-yl)-2-(4-nitrophenyl)ethylcarbamoyl]-2-phenylethyl}carbamicacid tert-butyl ester (4): To a solution of1-(S)-(4-ethylthiazol-2-yl)-2-(4-nitrophenyl)ethyl amine hydrobromide,3, (0.393 g, 1.1 mmol),(S)-(2-tert-butoxycarbonylamino)-3-phenylpropionic acid (0.220 g, 0.828mmol) and 1-hydroxybenzotriazole (HOBt) (0.127 g, 0.828 mmol) in DMF (10mL) at 0° C., is added 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide(EDCI) (0.159 g, 0.828 mmol) followed by diisopropylamine (0.204 g, 1.58mmol). The mixture is stirred at 0° C. for 30 minutes then at roomtemperature overnight. The reaction mixture is diluted with water andextracted with EtOAc. The combined organic phase is washed with 1 Naqueous HCl, 5% aqueous NaHCO₃, water and brine, and dried over Na₂SO₄.The solvent is removed in vacuo to afford 0.345 g of the desired productwhich is used without further purification. LC/MS ESI+ 525 (M+1).

Preparation of4-{(S)-2-[(S)-2-(tert-butoxycarbonylamino)-3-phenylpropanamido]-2-(4-ethylthiazol-2-yl)ethyl}phenylsulfamicacid ammonium salt (5):{1-[1-(4-ethylthiazol-2-yl)-2-(4-nitrophenyl)ethylcarbamoyl]-2-phenylethyl}carbamicacid tert-butyl ester, 4, (0.345 g) is dissolved in MeOH (4 mL). Acatalytic amount of Pd/C (10% w/w) is added and the mixture is stirredunder a hydrogen atmosphere 2 hours. The reaction mixture is filteredthrough a bed of CELITE™ and the solvent is removed under reducedpressure. The crude product is dissolved in pyridine (12 mL) and treatedwith SO₃-pyridine (0.314 g). The reaction is stirred at room temperaturefor 5 minutes after which a 7% solution of NH₄OH (50 mL) is added. Themixture is then concentrated and the resulting residue is purified byreverse phase chromatography to afford 0.222 g of the desired product asthe ammonium salt. ¹H NMR (CD₃OD): δ 7.50-6.72 (m, 10H), 5.44-5.42 (d,1H, J=6.0 Hz), 4.34 (s, 1H), 3.34-2.79 (m, 4H), 2.83-2.76 (q, 2H, J=7.2Hz), 1.40 (s, 9H), 1.31 (t, 3H, J=7.5 Hz).

The disclosed inhibitors can also be isolated as the free acid. Anon-limiting example of this procedure is described herein below inExample 4.

The following is a non-limiting example of compounds encompassed withinthis embodiment of the first aspect of Category I of the presentdisclosure.

4-{(S)-2-[(R)-2-(tert-butoxycarbonylamino)-3-phenylpropanamido]-2-(4-ethylthiazol-2-yl)ethyl}phenylsulfamicacid: ¹H NMR (CD₃OD): δ 7.22-7.02 (m, 10H), 5.39 (s, 1H), 4.34 (s, 1H),3.24-2.68 (m, 6H), 1.37 (s, 9H), 1.30 (t, 3H, J=7.5 Hz).

Another embodiment of this aspect of Category I relates to inhibitorshaving the formula:

wherein R units and R^(5a) units further described in Table II.

TABLE II No. R R^(5a) B26 thiazol-2-yl (S)-benzyl B274-methylthiazol-2-yl (S)-benzyl B28 4-ethylthiazol-2-yl (S)-benzyl B294-propylthiazol-2-yl (S)-benzyl B30 4-iso-propylthiazol-2-yl (S)-benzylB31 4-cyclopropylthiazol-2-yl (S)-benzyl B32 4-butylthiazol-2-yl(S)-benzyl B33 4-tert-butylthiazol-2-yl (S)-benzyl B344-cyclohexylthiazol-2-yl (S)-benzyl B354-(2,2,2-trifluoroethyl)thiazol-2-yl (S)-benzyl B364-(3,3,3-trifluoropropyl)thiazol-2-yl (S)-benzyl B374-(2,2-difluorocyclopropyl)thiazol-2-yl (S)-benzyl B384-(methoxymethyl)thiazol-2-yl (S)-benzyl B39 4-(carboxylic acid ethylester)thiazol-2-yl (S)-benzyl B40 4,5-dimethylthiazol-2-yl (S)-benzylB41 4-methyl-5-ethylthiazol-2-yl (S)-benzyl B42 4-phenylthiazol-2-yl(S)-benzyl B43 4-(4-chlorophenyl)thiazol-2-yl (S)-benzyl B444-(3,4-dimethylphenyl)thiazol-2-yl (S)-benzyl B454-methyl-5-phenylthiazol-2-yl (S)-benzyl B464-(thiophen-2-yl)thiazol-2-yl (S)-benzyl B474-(thiophen-3-yl)thiazol-2-yl (S)-benzyl B484-(5-chlorothiophen-2-yl)thiazol-2-yl (S)-benzyl B495,6-dihydro-4H-cyclopenta[d]thiazol-2-yl (S)-benzyl B504,5,6,7-tetrahydrobenzo[d]thiazol-2-yl (S)-benzyl

The compounds of this embodiment can be prepared according to theprocedure outlined above in Scheme I and described in Example 1 bysubstituting the appropriate Boc-β-amino acid for(S)-(2-tert-butoxycarbonylamino)-3-phenylpropionic acid in step (d).

The following are non-limiting examples of compounds according to thisembodiment.

{1-[1-(4-Ethylthiazol-2-yl)-(S)-2-(4-sulfoaminophenyl)ethylcarbamoyl]-(S)-2-phenylethyl}methylcarbamic acid tert-butyl ester: ¹H NMR (300 MHz, MeOH-d₄) δ 8.36 (d,J=8.1 Hz, 1H), 7.04-7.22 (m, 9H), 5.45 (s, 1H), 3.01-3.26 (m, 2H),2.60-2.88 (m, 4H), 2.33 (s, 3H), 1.30 (s, 9H).

{1-[1-(4-Phenylthiazol-2-yl)-(S)-2-(4-sulfoaminophenyl)ethylcarbamoyl]-(S)-2-phenylethyl}methylcarbamic acid tert-butyl ester: ¹H NMR (300 MHz, MeOH-d₄) δ 8.20 (d,J=8.1 Hz, 1H), 7.96-7.99 (m, 2H), 7.48-7.52 (m, 3H), 7.00-7.23 (m, 7H),6.89 (s, 1H), 5.28 (q, J=7.5 Hz, 1H), 4.33 (t, J=6.6 Hz, 1H), 3.09-3.26(m, 2H), 3.34 (dd, J=13.2 and 8.4 Hz, 1H), 2.82 (dd, J=13.2 and 8.4 Hz,1H), 1.38 (s, 9H).

The second aspect of Category I of the present disclosure relates tocompounds wherein R is a substituted or unsubstituted thiazol-4-ylhaving the formula:

one embodiment of which relates to inhibitors having the formula:

wherein R units and R^(5a) units further described in Table III.

TABLE III No. R R^(5a) C51 thiazol-4-yl (S)-benzyl C522-methylthiazol-4-yl (S)-benzyl C53 2-ethylthiazol-4-yl (S)-benzyl C542-propylthiazol-4-yl (S)-benzyl C55 2-iso-propylthiazol-4-yl (S)-benzylC56 2-cyclopropylthiazol-4-yl (S)-benzyl C57 2-butylthiazol-4-yl(S)-benzyl C58 2-tert-butylthiazol-4-yl (S)-benzyl C592-cyclohexylthiazol-4-yl (S)-benzyl C602-(2,2,2-trifluoroethyl)thiazol-4-yl (S)-benzyl C612-(3,3,3-trifluoropropyl)thiazol-4-yl (S)-benzyl C622-(2,2-difluorocyclopropyl)thiazol-4-yl (S)-benzyl C632-phenylthiazol-4-yl (S)-benzyl C64 2-(4-chlorophenyl)thiazol-4-yl(S)-benzyl C65 2-(3,4-dimethylphenyl)thiazol-4-yl (S)-benzyl C662-(thiophen-2-yl)thiazol-4-yl (S)-benzyl C672-(thiophen-3-yl)thiazol-4-yl (S)-benzyl C682-(3-chlorothiophen-2-yl)thiazol-4-yl (S)-benzyl C692-(3-methylthiophen-2-yl)thiazol-4-yl (S)-benzyl C702-(2-methylthiazol-4-yl)thiazol-4-yl (S)-benzyl C712-(furan-2-yl)thiazol-4-yl (S)-benzyl C72 2-(pyrazin-2-yl)thiazol-4-yl(S)-benzyl C73 2-[(2-methyl)pyridin-5-yl]thiazol-4-yl (S)-benzyl C742-(4-chlorobenzenesulfonylmethyl)thiazol-4-yl (S)-benzyl C752-(tert-butylsulfonylmethyl)thiazol-4-yl (S)-benzyl

The compounds encompassed within the second aspect of Category I of thepresent disclosure can be prepared by the procedure outlined in SchemeII and described in Example 2 herein below.

EXAMPLE 2(4-((S)-2-((S)-2-((tert-Butoxycarbonyl)amino)-3-phenylpropanamido)-2-(2-phenylthiazol-4-yl)ethyl)phenyl)sulfamicacid (9)

Preparation of (S)-[3-diazo-1-(4-nitrobenzyl)-2-oxo-propyl]-carbamicacid tert-butyl ester (6): To a 0° C. solution of2-(S)-tert-butoxycarbonylamino-3-(4-nitrophenyl)-propionic acid (1.20 g,4.0 mmol) in THF (20 mL) is added dropwise triethylamine (0.61 mL, 4.4mmol) followed by iso-butyl chloroformate (0.57 mL, 4.4 mmol). Thereaction mixture is stirred at 0° C. for 20 minutes and filtered. Thefiltrate is treated with an ether solution of diazomethane (˜16 mmol) at0° C. The reaction mixture is stirred at room temperature for 3 hoursthen concentrated in vacuo. The resulting residue is dissolved in EtOAcand washed successively with water and brine, dried (Na₂SO₄), filteredand concentrated. The residue is purified over silica (hexane/EtOAc 2:1)to afford 1.1 g (82% yield) of the desired product as a slightly yellowsolid. ¹H NMR (300 MHz, CDCl₃) δ 8.16 (d, J=8.7 Hz, 2H), 7.39 (d, J=8.7Hz, 2H), 5.39 (s, 1H), 5.16 (d, J=6.3 Hz, 1H), 4.49 (s, 1H), 3.25 (dd,J=13.8 and 6.6, 1H), 3.06 (dd, J=13.5 and 6.9 Hz, 1H), 1.41 (s, 9H).

Preparation of (S)-tert-butyl4-bromo-1-(4-nitrophenyl)-3-oxobutan-2-ylcarbamate (7): To a 0° C.solution of (S)-[3-diazo-1-(4-nitrobenzyl)-2-oxo-propyl]-carbamic acidtert-butyl ester, 6, (0.350 g, 1.04 mmol) in THF (5 mL) is addeddropwise 48% aq. HBr (0.14 mL, 1.25 mmol). The reaction mixture isstirred at 0° C. for 1.5 hours then the reaction is quenched at 0° C.with sat. Na₂CO₃. The mixture is extracted with EtOAc (3×25 mL) and thecombined organic extracts are washed with brine, dried (Na₂SO₄),filtered and concentrated to obtain 0.400 g of the product which is usedin the next step without further purification. ¹H NMR (300 MHz, CDCl₃) δ8.20 (d, J=8.4 Hz, 2H), 7.39 (d, J=8.4 Hz, 2H), 5.06 (d, J=7.8 Hz, 1H),4.80 (q, J=6.3 Hz, 1H), 4.04 (s, 2H), 1.42 (s, 9H).

Preparation of tert-butyl(S)-1-(S)-2-(4-nitrophenyl)-1-(2-phenylthiazole-4-yl)ethylamino-1-oxo-3-phenylpropan-2-ylcarbamate(8): A mixture of thiobenzamide (0.117 g, 0.85 mmol) and (S)-tert-butyl4-bromo-1-(4-nitrophenyl)-3-oxobutan-2-ylcarbamate, 7, (0.300 g, 0.77mmol) in CH₃CN (4 mL) is refluxed 2 hours. The reaction mixture iscooled to room temperature and diethyl ether is added to precipitate theintermediate 2-(nitrophenyl)-(S)-1-(4-phenylthiazol-2-yl)ethylaminewhich is isolated by filtration as the hydrobromide salt. Thehydrobromide salt is dissolved in DMF (3 mL) together withdiisoproylethylamine (0.42 mL, 2.31 mmol), 1-hydroxybenzotriazole (0.118g, 0.79 mmol) and (S)-(2-tert-butoxycarbonyl-amino)-3-phenylpropionicacid (0.212 g, 0.80 mmol). The mixture is stirred at 0° C. for 30minutes then at room temperature overnight. The reaction mixture isdiluted with water and extracted with EtOAc. The combined organic phaseis washed with 1 N aqueous HCl, 5% aqueous NaHCO₃, water and brine, anddried over Na₂SO₄. The solvent is removed in vacuo to afford 0.395 g(90% yield) of the desired product which is used without furtherpurification. LC/MS ESI+ 573 (M+1).

Preparation of(4-((S)-2-((S)-2-((tert-Butoxycarbonyl)amino)-3-phenyl-propanamido)-2-(2-phenylthiazol-4-yl)ethyl)phenyl)sulfamicacid (9): tert-butyl(S)-1-(S)-2-(4-nitrophenyl)-1-(2-phenylthiazole-4-yl)ethylamino-1-oxo-3-phenylpropan-2-ylcarbamate,8, (0.360 g) is dissolved in MeOH (4 mL). A catalytic amount of Pd/C(10% w/w) is added and the mixture is stirred under a hydrogenatmosphere 12 hours. The reaction mixture is filtered through a bed ofCELITE™ and the solvent is removed under reduced pressure. The crudeproduct is dissolved in pyridine (12 mL) and treated with SO₃-pyridine(0.296 g). The reaction is stirred at room temperature for 5 minutesafter which a 7% solution of NH₄OH (10 mL) is added. The mixture is thenconcentrated and the resulting residue is purified by reverse phasechromatography to afford 0.050 g of the desired product as the ammoniumsalt. ¹H NMR (300 MHz, MeOH-d₄) δ 8.20 (d, J=8.1 Hz, 1H), 7.96-7.99 (m,2H), 7.48-7.52 (m, 3H), 7.00-7.23 (m, 7H), 6.89 (s, 1H), 5.28 (q, J=7.5Hz, 1H), 4.33 (t, J=6.6 Hz, 1H), 3.09-3.26 (m, 2H), 3.34 (dd, J=13.2 and8.4 Hz, 1H), 2.82 (dd, J=13.2 and 8.4 Hz, 1H), 1.38 (s, 9H).

The first aspect of Category II of the present disclosure relates tocompounds wherein R is a substituted or unsubstituted thiazol-4-yl unithaving the formula:

one embodiment of which relates to inhibitors having the formula:

wherein R units are thiazol-4-yl units, that when substituted, aresubstituted with R⁴ units. R and R^(5a) units are further described inTable IV.

TABLE IV No. R R^(5a) D76 thiazol-4-yl (S)-benzyl D772-methylthiazol-4-yl (S)-benzyl D78 2-ethylthiazol-4-yl (S)-benzyl D792-propylthiazol-4-yl (S)-benzyl D80 2-iso-propylthiazol-4-yl (S)-benzylD81 2-cyclopropylthiazol-4-yl (S)-benzyl D82 2-butylthiazol-4-yl(S)-benzyl D83 2-tert-butylthiazol-4-yl (S)-benzyl D842-cyclohexylthiazol-4-yl (S)-benzyl D852-(2,2,2-trifluoroethyl)thiazol-4-yl (S)-benzyl D862-(3,3,3-trifluoropropyl)thiazol-4-yl (S)-benzyl D872-(2,2-difluorocyclopropyl)thiazol-4-yl (S)-benzyl D882-phenylthiazol-4-yl (S)-benzyl D89 2-(4-chlorophenyl)thiazol-4-yl(S)-benzyl D90 2-(3,4-dimethylphenyl)thiazol-4-yl (S)-benzyl D912-(thiophen-2-yl)thiazol-4-yl (S)-benzyl D922-(thiophen-3-yl)thiazol-4-yl (S)-benzyl D932-(3-chlorothiophen-2-yl)thiazol-4-yl (S)-benzyl D942-(3-methylthiophen-2-yl)thiazol-4-yl (S)-benzyl D952-(2-methylthiazol-4-yl)thiazol-4-yl (S)-benzyl D962-(furan-2-yl)thiazol-4-yl (S)-benzyl D97 2-(pyrazin-2-yl)thiazol-4-yl(S)-benzyl D98 2-[(2-methyl)pyridin-5-yl]thiazol-4-yl (S)-benzyl D992-(4-chlorobenzenesulfonylmethyl)thiazol-4-yl (S)-benzyl D1002-(tert-butylsulfonylmethyl)thiazol-4-yl (S)-benzyl

The compounds encompassed within the second aspect of Category II of thepresent disclosure can be prepared by the procedure outlined in SchemeIII and described in Example 3 herein below.

EXAMPLE 34-{(S)-2-[(S)-2-(Methoxycarbonylamino)-3-phenylpropanamido]-2-(2-ethylthiazol-4-yl)ethyl}phenylsulfamic acid (13)

Preparation of methyl(S)-1-[(S)-1-(2-ethylthiazole-4-yl)-2-(4-nitrophenyl)-ethyl]amino-1-oxo-3-phenylpropane-2-ylcarbamate(12): A mixture of propanethioamide (69 mg, 0.78 mmol) and(S)-tert-butyl 4-bromo-1-(4-nitrophenyl)-3-oxobutan-2-ylcarbamate, 7,(0.300 g, 0.77 mmol) in CH₃CN (4 mL) is refluxed for 2 hours. Thereaction mixture is cooled to room temperature and diethyl ether isadded to precipitate the intermediate2-(nitrophenyl)-(S)-1-(4-ethylthiazol-2-yl)ethylamine which is isolatedby filtration as the hydrobromide salt. The hydrobromide salt isdissolved in DMF (8 mL) together with diisoproylethylamine (0.38 mL,2.13 mmol), 1-hydroxybenzotriazole (107 mg, 0.71 mmol) and(S)-(2-methoxycarbonyl-amino)-3-phenylpropionic acid (175 mg, 0.78mmol). The mixture is stirred at 0° C. for 30 minutes then at roomtemperature overnight. The reaction mixture is diluted with water andextracted with EtOAc. The combined organic phase is washed with 1 Naqueous HCl, 5% aqueous NaHCO₃, water and brine, and dried over Na₂SO₄.The solvent is removed in vacuo to afford 0.300 g (81% yield) of thedesired product which is used without further purification. LC/MS ESI+MS 483 (M+1).

Preparation of4-((S)-2-((S)-2-(methoxycarbonylamino)-3-phenylpropanamido)-2-(2-ethylthiazol-4-yl)ethyl)phenylsulfamicacid ammonium salt (13): tert-Butyl(5)-1-(S)-2-(4-nitrophenyl)-1-(2-ethylthiazole-4-yl)ethylamino-1-oxo-3-phenylpropan-2-ylcarbamate,12, (0.300 g) is dissolved in MeOH (4 mL). A catalytic amount of Pd/C(10% w/w) is added and the mixture is stirred under a hydrogenatmosphere 18 hours. The reaction mixture is filtered through a bed ofCELITE™ and the solvent is removed under reduced pressure. The crudeproduct is dissolved in pyridine (12 mL) and treated with SO₃-pyridine(223 mg, 1.40 mmol). The reaction is stirred at room temperature for 5minutes after which a 7% solution of NH₄OH (12 mL) is added. The mixtureis then concentrated and the resulting residue is purified by reversephase chromatography to afford 25 mg of the desired product as theammonium salt. ¹H NMR (300 MHz, MeOH-d₄) δ 7.14-7.24 (m, 6H), 6.97-7.0(m, 4H), 6.62 (s, 1H), 5.10-5.30 (m, 1H), 4.36 (t, J=7.2 Hz, 1H), 3.63(s, 3H), 3.14 (dd, J=13.5 and 6.3 Hz, 1H), 2.93-3.07 (m, 5H), 2.81 (dd,J=13.5 and 6.3 HZ, 1H), 1.39 (t, J=7.8 Hz, 3H).

In another iteration of the process of the present disclosure, compound13, as well as the other analogs which comprise the present disclosure,can be isolated as the free acid by adapting the procedure describedherein below.

EXAMPLE 44-((S)-2-((S)-2-(Methoxycarbonylamino)-3-phenylpropanamido)-2-(2-ethylthiazol-4-yl)ethyl)phenylsulfamic acid [Free Acid Form] (13)

Preparation of{1-[2-(S)-(4-(S)-aminophenyl)-1-(2-ethylthiazol-4-yl)ethyl-carbamoyl]-2-phenylethyl}-carbamicacid methyl ester (12a): A Parr hydrogenation vessel is charged withtert-butyl(S)-1-(S)-2-(4-nitrophenyl)-1-(2-ethylthiazole-4-yl)ethylamino-1-oxo-3-phenylpropan-2-ylcarbamate,12, (18.05 g, 37.4 mmol, 1.0 eq) and Pd/C (10% Pd on C, 50% wet,Degussa-type E101 NE/W, 2.68 g, 15 wt %) as solids. MeOH (270 mL, 15mL/g) is added to provide a suspension. The vessel is put on a Parrhydrogenation apparatus. The vessel is submitted to a fill/vacuumevacuate process with N₂ (3×20 psi) to inert, followed by the sameprocedure with H₂ (3×40 psi). The vessel is filled with H₂ and thevessel is shaken under 40 psi H₂ for ˜40 hr. The vessel is evacuated andthe atmosphere is purged with N₂ (5×20 psi). An aliquot is filtered andanalyzed by HPLC to insure complete conversion. The suspension isfiltered through a pad of celite to remove the catalyst, and thehomogeneous yellow filtrate is concentrated by rotary evaporation toafford 16.06 g (95% yield) of the desired product as a tan solid, whichis used without further purification.

Preparation of4-((S)-2-((S)-2-(methoxycarbonyl)-3-phenylpropanamido)-2-(2-ethylthiazol-4-yl)ethyl)phenylsulfamicacid (13): A 100 mL RBF is charged with{1-[2-(S)-(4-(S)-aminophenyl)-1-(2-ethylthiazol-4-yl)ethyl-carbamoyl]-2-phenylethyl}-carbamicacid methyl ester, 12a, (10.36 g, 22.9 mmol, 1.0 eq.) prepared in thestep described herein above. Acetonitrile (50 mL, 5 mL/g) is added andthe yellow suspension is stirred at room temperature. A second 3-necked500 mL RBF is charged with SO₃.pyr (5.13 g, 32.2 mmol, 1.4 eq.) andacetonitrile (50 mL 5 mL/g) and the white suspension is stirred at roomtemperature. Both suspensions are gently heated until the reactionsolution containing{1-[2-(S)-(4-(S)-aminophenyl)-1-(2-ethylthiazol-4-yl)ethyl-carbamoyl]-2-phenylethyl}-carbamicacid methyl ester becomes red-orange in color (typically for thisexample about 44° C.). This substrate containing solution is poured inone portion into the stirring suspension of SO₃.pyr at 35° C. Theresulting opaque mixture (39° C.) is stirred vigorously while allowed toslowly cool to room temperature. After stirring for 45 min, the reactionis determined to be complete by HPLC. H₂O (200 mL, 20 mL/g) is added tothe orange suspension to provide a yellow-orange homogeneous solutionhaving a pH of approximately 2.4. Concentrated H₃PO₄ is added slowlyover 12 minutes to lower the pH to approximately 1.4. During this pHadjustment, an off-white precipitate is formed and the solution isstirred at room temperature for 1 hr. The suspension is filtered and thefilter cake is washed with the filtrate. The filter cake is air-dried onthe filter overnight to afford 10.89 g (89% yield) of the desiredproduct as a tan solid.

The following are further non-limiting examples of the second aspect ofCategory II of the present disclosure.

4-{(S)-2-[(S)-2-(Methoxycarbonylamino)-3-phenylpropanamido]-2-(2-methylthiazol-4-yl)ethyl}phenylsulfamicacid: ¹H NMR (300 MHz, MeOH-d₄) δ 8.15 (d, J=8.4 Hz, 1H), 7.16-7.25 (m,5H), 6.97-7.10 (m, 4H), 6.61 (s, 1H), 5.00-5.24 (m, 1H), 4.36 (t, J=7.2Hz, 1H), 3.64 (s, 2H), 3.11-3.19 (s, 1H), 2.92-3.04 (s, 2H), 2.81 (dd,J=13.5 and 8.1 Hz, 1H), 2.75 (s, 3H).

4-{(S)-2-(2-Ethylthiazole-4-yl)-2-[(S)-2-(methoxycarbonylamino)-3-phenylpropan-amido]ethyl}phenylsulfamicacid: ¹H NMR (300 MHz, MeOH-d₄) δ 7.16-7.29 (m, 5H), 7.02-7.12 (m, 4H),6.83 (s, 1H), 5.10-5.35 (m, 1H), 3.52-3.67 (m, 3H), 3.18-3.25 (m, 2H),3.05 (q, J=7.5 Hz, 2H), 2.82-2.95 (m, 2H), 2.65 (s, 3H), 1.39 (t, J=7.5Hz, 3H).

4-{(S)-2-(2-Isopropylthiazol-4-yl)-2-[(S)-2-(methoxycarbonylamino)-3-phenylpropan-amido]ethyl}phenylsulfamicacid: ¹H NMR (CD₃OD) δ 8.16 (d, 1H, J=8.7Hz), 7.22-7.13 (m, 3H), 7.07(d, 1H, J=8.4 Hz), 6.96 (d, 1H, J=8.1Hz), 6.62 (s, 1H), 5.19 (t, 1H,J=7.2Hz), 4.36 (t, 1H, J=7.8Hz), 3.63 (s, 3H), 3.08 (1H, A of ABX,J=3.6, 14.5Hz), 2.99 (1H, B of ABX, J=7.2, 13.8Hz), 2.85-2.78 (m, 1H),1.41 (d, 6H, J=6.9Hz).

4-{(S)-2-(2-Cyclopropylthiazol-4-yl)-2-[(S)-2-(methoxycarbonylamino)-3-phenylpropanamido]ethyl}phenylsulfamicacid: ¹H NMR (CD₃OD): δ 7.15-7.02 (m, 5H), 6.96-6.93 (d, 2H, J=8.4 Hz),6.86-6.83 (d, 2H, J=8.3 Hz), 6.39 (s, 1H), 5.01 (t, 1H, J=5.0 Hz), 4.22(t, 1H, J=7.4 Hz), 3.51 (s, 3H), 2.98-2.69 (m, 2H), 2.22-2.21 (m, 1H),1.06-1.02 (m, 2H), 0.92-0.88 (m, 2H).

4-{(S)-2-{2-[(4-Chlorophenylsulfonyl)methyl]thiazol-4-yl}-2-[(S)-2-(methoxy-carbonylamino)-3-phenylpropanamido]ethyl}phenylsulfamicacid: ¹H NMR (CD₃OD): δ 7.96-7.93 (d, 2H, J=8.6 Hz), 7.83-7.80 (d, 2H,J=8.6 Hz), 7.44-7.34 (m, 5H), 7.29-7.27 (d, 2H, J=8.4 Hz), 7.14-7.11 (d,2H, J=8.4 Hz), 6.97 (s, 1H), 5.31 (t, 1H, J=6.8 Hz), 5.22-5.15 (m, 2H),4.55 (t, 1H, J=7.3 Hz), 3.84 (s, 3H), 3.20-2.96 (m, 4H).

4-{(S)-2-[2-(tert-Butylsulfonylmethyl)thiazol-4-yl]-2-[(S)-2-(methoxycarbonylamino)-3-phenylpropanamido]ethyl}phenylsulfamicacid: ¹H NMR (CD₃OD): δ 7.40-7.30 (m, 5H), 7.21-7.10 (m, 4H), 7.02 (s,1H), 5.37 (t, 1H, J=6.9 Hz), 5.01-4.98 (m, 2H), 4.51 (t, 1H, J=7.1 Hz),3.77 (s, 3H), 3.34-2.91 (m, 4H), 1.58 (s, 9H).

4-{(S)-2-[(S)-2-(Methoxycarbonylamino)-3-phenylpropionamido]-2-(2-phenylthiazol-4-yl)ethyl}phenylsulfamicacid: ¹H NMR (300 MHz, DMSO-d₆) δ 7.96-7.99 (m, 2H), 7.51-7.56 (m, 3H),7.13-7.38 (m, 6H), 6.92-6.95 (m, 4H), 5.11-5.16 (m, 1H), 4.32-4.35 (m,1H), 3.51 (s, 3H), 3.39-3.40 (m, 2H), 3.09-3.19 (m, 1H), 2.92-3.02 (m,2H), 2.75 (dd, J=10.5 Hz and 9.9 Hz, 1H).

4-{(S)-2-[(S)-2-(Methoxycarbonylamino)-3-phenylpropanamido]-2-[2-(thiophen-2-yl)thiazol-4-yl]ethyl}phenylsulfamicacid: ¹H NMR (CD₃OD): δ 7.61-7.56 (m, 2H), 7.25-7.01 (m, 10H), 6.75 (s,1H), 5.24-5.21 (q, 1H, J=7.2 Hz), 4.38 (t, 1H, J=7.2 Hz), 3.60 (s, 3H),3.23-3.14 (m, 1H), 3.08-3.00 (m, 2H), 2.87-2.80 (m, 1H).

4-{(S)-2-[2-(3-Chlorothiophen-2-yl)thiazol-4-yl]-2-[(S)-2-(methoxycarbonylamino)-3-phenylpropanamido]ethyl}phenylsulfamicacid: ¹H NMR (CD₃OD): δ 7.78-7.76 (d, 1H, J=5.4 Hz), 7.36-7.14 (m, 10H),7.03 (s, 1H), 5.39 (t, 1H, J=6.9 Hz), 4.54 (t, 1H, J=7.3 Hz), 3.80 (s,3H), 3.39-2.98 (m, 4H).

4-{(S)-2-[(S)-2-(Methoxycarbonylamino)-3-phenylpropanamido]-2-[2-(3-methylthiophen-2-yl)thiazol-4-yl]ethyl}phenylsulfamicacid: ¹H NMR (CD₃OD): δ 7.38 (d, 1H, J=5.1 Hz), 7.15-6.93 (m, 10H), 6.73(s, 1H), 5.17 (t, 1H, J=6.9 Hz), 4.31 (t, 1H, J=7.3 Hz), 3.57 (s, 3H),3.18-3.11 (m, 1H), 3.02-2.94 (m, 2H), 2.80-2.73 (m, 1H), 2.46 (s, 3H).

4-((S)-2-(2-(Furan-2-yl)thiazol-4-yl)-2-((S)-2-((methoxycarbonyl)amino)-3-phenylpropanamido)ethyl)phenylsulfamicacid: ¹H NMR (CD₃OD): δ 7.54-7.46 (m, 1H), 7.02-6.79 (m, 10H), 6.55-6.51(m, 1H), 6.44-6.41 (m, 1H), 5.02-5.00 (q, 1H, J=6.4 Hz), 4.16-4.14 (q,1H, J=7.1 Hz), 3.43 (s, 3H), 2.96-2.58 (m, 4H).

4-{(S)-2-[(S)-2-(Methoxycarbonylamino)-3-phenylpropanamido]-2-[2-(2-methylthiazole-4-yl)thiazol-4yl]ethyl}phenylsulfamicacid: ¹H NMR (300 MHz, MeOH-d₄) δ 8.27 (d, J=5.4 Hz, 1H), 7.97 (s, 1H),6.99-7.21 (m, 8H), 5.18-5.30 (m, 1H), 4.30-4.39 (m, 1H), 3.64 (s, 3H),3.20 (dd, J=14.1 and 6.6 Hz, 1H), 2.98-3.08 (m, 2H), 2.84 (dd, J=14.1and 6.6 Hz, 1H), 2.78 (s, 3H).

4-{(S)-2-[(S)-2-(Methoxycarbonylamino)-3-phenylpropanamido]-2-[(2-pyrazin-2-yl)thiazol-4-yl]ethyl}phenylsulfamicacid: ¹H NMR (300 MHz, MeOH-d₄) δ 9.34 (s, 1H), 8.65 (s, 2H), 8.34 (d,J=8.1 Hz, 1H), 7.00-5.16 (m. 9H), 5.30 (q, J=7.2 Hz, 1H), 4.41 (t, J=7.2Hz, 1H), 3.65 (s, 3H), 3.23 (dd, J=13.8 and 6.9 Hz, 1H), 2.98-3.13 (m,2H), 2.85 (dd, J=13.8 and 6.9 Hz, 1H).

4-{(S)-2-[(S)-2-(Methoxycarbonylamino)-3-phenylpropanamido]-2-[2-(6-methylpyridin-3-yl)thiazol-4-yl]ethyl}phenylsulfamicacid: ¹H NMR (CD₃OD): δ 8.90 (s, 1H), 8.19-8.13 (m, 1H), 7.39-7.36 (d,1H, J=8.2 Hz), 7.07-6.88 (m, 9H), 6.79 (s, 1H), 5.17 (t, 1H, J=7.0 Hz),4.29 (t, 1H, J=7.4 Hz), 3.54 (s, 3H), 3.10-2.73 (m, 4H), 2.53 (s, 3H).

Category III of the present disclosure relates to compounds wherein R isa substituted or unsubstituted thiazol-2-yl unit having the formula:

one embodiment of which relates to inhibitors having the formula:

wherein R units are thiazol-2-yl units, that when substituted, aresubstituted with R² and R³ units. R and R^(5a) units are furtherdescribed in Table V.

TABLE V No. R R^(5a) E101 thiazol-2-yl (S)-benzyl E1024-methylthiazol-2-yl (S)-benzyl E103 4-ethylthiazol-2-yl (S)-benzyl E1044-propylthiazol-2-yl (S)-benzyl E105 4-iso-propylthiazol-2-yl (S)-benzylE106 4-cyclopropylthiazol-2-yl (S)-benzyl E107 4-butylthiazol-2-yl(S)-benzyl E108 4-tert-butylthiazol-2-yl (S)-benzyl E1094-cyclohexylthiazol-2-yl (S)-benzyl E1104-(2,2,2-trifluoroethyl)thiazol-2-yl (S)-benzyl E1114-(3,3,3-trifluoropropyl)thiazol-2-yl (S)-benzyl E1124-(2,2-difluorocyclopropyl)thiazol-2-yl (S)-benzyl E1134-(methoxymethyl)thiazol-2-yl (S)-benzyl E114 4-(carboxylic acid ethylester)thiazol-2-yl (S)-benzyl E115 4,5-dimethylthiazol-2-yl (S)-benzylE116 4-methyl-5-ethylthiazol-2-yl (S)-benzyl E117 4-phenylthiazol-2-yl(S)-benzyl E118 4-(4-chlorophenyl)thiazol-2-yl (S)-benzyl E1194-(3,4-dimethylphenyl)thiazol-2-yl (S)-benzyl E1204-methyl-5-phenylthiazol-2-yl (S)-benzyl E1214-(thiophen-2-yl)thiazol-2-yl (S)-benzyl E1224-(thiophen-3-yl)thiazol-2-yl (S)-benzyl E1234-(5-chlorothiophen-2-yl)thiazol-2-yl (S)-benzyl E1245,6-dihydro-4H-cyclopenta[d]thiazol-2-yl (S)-benzyl E1254,5,6,7-tetrahydrobenzo[d]thiazol-2-yl (S)-benzyl

The compounds encompassed within Category III of the present disclosurecan be prepared by the procedure outlined in Scheme IV and described inExample 5 herein below.

EXAMPLE 54-[(S)-2-((S)-2-Acetamido-3-phenylpropanamido)-2-(4-ethylthiazol-2-yl)ethyl]phenylsulfamicacid (15)

Preparation of(S)-2-acetamido-N-[(S)-1-(4-ethylthiazol-2-yl)-2-(4-nitrophenyl)-ethyl]-3-phenylpropanamide(14): To a solution of1-(S)-(4-ethylthiazol-2-yl)-2-(4-nitrophenyl)ethyl amine hydrobromide,3, (0.343 g, 0.957 mmol), N-acetyl-L-phenylalanine (0.218 g),1-hydroxybenzotriazole (HOBt) (0.161 g), diisopropyl-ethylamine (0.26g), in DMF (10 mL) at 0°, is added1-(3-dimethylaminopropyl)-3-ethylcarbodiimide (EDCI) (0.201 g). Themixture is stirred at 0° C. for 30 minutes then at room temperatureovernight. The reaction mixture is diluted with water and extracted withEtOAc. The combined organic phase is washed with 1 N aqueous HCl, 5%aqueous NaHCO₃, water and brine, and dried over Na₂SO₄. The solvent isremoved in vacuo to afford 0.313 g (70% yield) of the desired productwhich is used without further purification. LC/MS ESI+ 467 (M+1).

Preparation of4-((S)-2-((S)-2-acetamido-3-phenylpropanamido)-2-(4-ethylthiazol-2-yl)ethyl)phenylsulfamicacid (15):(S)-2-Acetamido-N—[(S)-1-(4-ethylthiazol-2-yl)-2-(4-nitrophenyl)ethyl]-3-phenylpropanamide,14, (0.313 g) is dissolved in MeOH (4 mL). A catalytic amount of Pd/C(10% w/w) is added and the mixture is stirred under a hydrogenatmosphere 2 hours. The reaction mixture is filtered through a bed ofCELITE™ and the solvent is removed under reduced pressure. The crudeproduct is dissolved in pyridine (12 mL) and treated with SO₃-pyridine(0.320 g). The reaction is stirred at room temperature for 5 minutesafter which a 7% solution of NH₄OH (30 mL) is added. The mixture is thenconcentrated and the resulting residue is purified by reverse phasechromatography to afford 0.215 g of the desired product as the ammoniumsalt. ¹H NMR (CD₃OD): δ 7.23-6.98 (m, 10H), 5.37 (t, 1H), 4.64 (t, 1H,J=6.3 Hz), 3.26-2.74 (m, 6H), 1.91 (s, 3H), 1.29 (t, 3H, J=7.5 Hz).

The following are further non-limiting examples of compounds encompassedwithin Category III of the present disclosure.

4-[(S)-2-((S)-2-Acetamido-3-phenylpropanamido)-2-(4-tert-butylthiazol-2-yl)ethyl]phenylsulfamicacid: ¹H NMR (300 MHz, CD₃OD): δ 7.22-7.17 (m, 5H), 7.06 (dd, J=14.1,8.4 Hz, 4H), 6.97 (d, J=0.9 Hz, 1H), 5.39 (dd, J=8.4, 6.0 Hz, 1H), 4.65(t, J=7.2 Hz, 1H), 3.33-3.26 (m, 1H), 3.13-3.00 (m, 3H), 2.80 (dd,J=13.5, 8.7 Hz, 1H), 1.91 (s, 3H), 1.36 (s, 9H).

4-{(S)-2-((S)-2-Acetamido-3-phenylpropanamido)-2-[4-(thiophen-3-yl)thiazol-2-yl]ethyl)phenylsulfamicacid: ¹H NMR (300 MHz, CD₃OD): δ 8.58 (d, J=8.1 Hz, 1H), 7.83-7.82 (m,1H), 7.57-7.46 (m, 3H), 7.28-6.93 (m, 11H), 5.54-5.43 (m, 1H), 4.69-4.55(m, 2H), 3.41-3.33 (m, 1H), 3.14-3.06 (3H), 2.86-2.79 (m, 1H), 1.93 (s,3H).

The first aspect of Category IV of the present disclosure relates tocompounds wherein R is a substituted or unsubstituted thiazol-2-yl unithaving the formula:

one embodiment of which relates to inhibitors having the formula:

wherein R units and R^(5a) units further described in Table VI.

TABLE VI No. R R^(5a) F126 thiazol-2-yl hydrogen F1274-methylthiazol-2-yl hydrogen F128 4-ethylthiazol-2-yl hydrogen F1294-propylthiazol-2-yl hydrogen F130 4-iso-propylthiazol-2-yl hydrogenF131 4-cyclopropylthiazol-2-yl hydrogen F132 4-butylthiazol-2-ylhydrogen F133 4-tert-butylthiazol-2-yl hydrogen F1344-cyclohexylthiazol-2-yl hydrogen F135 4,5-dimethylthiazol-2-yl hydrogenF136 4-methyl-5-ethylthiazol-2-yl hydrogen F137 4-phenylthiazol-2-ylhydrogen F138 thiazol-2-yl (S)-iso-propyl F139 4-methylthiazol-2-yl(S)-iso-propyl F140 4-ethylthiazol-2-yl (S)-iso-propyl F1414-propylthiazol-2-yl (S)-iso-propyl F142 4-iso-propylthiazol-2-yl(S)-iso-propyl F143 4-cyclopropylthiazol-2-yl (S)-iso-propyl F1444-butylthiazol-2-yl (S)-iso-propyl F145 4-tert-butylthiazol-2-yl(S)-iso-propyl F146 4-cyclohexylthiazol-2-yl (S)-iso-propyl F1474,5-dimethylthiazol-2-yl (S)-iso-propyl F1484-methyl-5-ethylthiazol-2-yl (S)-iso-propyl F149 4-phenylthiazol-2-yl(S)-iso-propyl F150 4-(thiophen-2-yl)thiazol-2-yl (S)-iso-propyl

The compounds encompassed within Category IV of the present disclosurecan be prepared by the procedure outlined in Scheme V and described inExample 6 herein below.

EXAMPLE 64-{(S)-2-[(S)-2-(tert-Butoxycarbonylamino)-3-methylbutanamido]-2-(4-ethylthiazol-2-yl)ethyl}phenylsulfamicacid (17)

Preparation of tert-butyl(S)-1-[(S)-(4-ethylthiazol-2-yl)-2-(4-nitrophenyl)ethylamino]-3-methyl-1-oxobutan-2-ylcarbamate(16): To a solution of1-(5)-(4-ethylthiazol-2-yl)-2-(4-nitrophenyl)ethyl amine hydrobromide,3, (0.200 g, 0.558 mmol),(S)-(2-tert-butoxycarbonylamino)-3-methylbutyric acid (0.133 g) and1-hydroxybenzo-triazole (HOBt) (0.094 g) in DMF (5 mL) at 0°, is added1-(3-dimethylaminopropyl)-3-ethylcarbodiimide (EDCI) (0.118 g) followedby diisopropylamine (0.151 g). The mixture is stirred at 0° C. for 30minutes then at room temperature overnight. The reaction mixture isdiluted with water and extracted with EtOAc. The combined organic phaseis washed with 1 N aqueous HCl, 5% aqueous NaHCO₃, water and brine, anddried over Na₂SO₄. The solvent is removed in vacuo to afford 0.219 g(82% yield) of the desired product which is used without furtherpurification. LC/MS ESI+ 477 (M+1).

Preparation of4-{(S)-2-[(S)-2-(tert-butoxycarbonylamino)-3-methylbutanamido]-2-(4-ethylthiazol-2-yl)ethyl}phenylsulfamicacid (17): tert-Butyl(S)-1-[(S)-(4-ethylthiazol-2-yl)-2-(4-nitrophenyl)ethylamino]-3-methyl-1-oxobutan-2-ylcarbamate,16, (0.219 g) is dissolved in MeOH (4 mL). A catalytic amount of Pd/C(10% w/w) is added and the mixture is stirred under a hydrogenatmosphere 2 hours. The reaction mixture is filtered through a bed ofCELITE™ and the solvent is removed under reduced pressure. The crudeproduct is dissolved in pyridine (5 mL) and treated with SO₃-pyridine(0.146 g). The reaction is stirred at room temperature for 5 minutesafter which a 7% solution of NH₄OH (30 mL) is added. The mixture is thenconcentrated and the resulting residue is purified by reverse phasechromatography to afford 0.148 g of the desired product as the ammoniumsalt. ¹H NMR (CD₃OD): δ 7.08 (s, 4H), 7.02 (s, 1H), 5.43 (s, 1H), 3.85(s, 1H), 3.28-2.77 (m, 4H), 1.94 (s, 1H), 1.46 (s, 9H), 1.29 (s, 3H,J=7.3 Hz), 0.83 (s, 6H).

The following are further non-limiting examples of the second aspect ofCategory IV of the present disclosure.

(S)-4-{2-[2-(tert-Butoxycarbonyl)acetamide]-2-(4-ethylthiazol-2-yl)ethyl}phenyl-sulfamicacid: ¹H NMR (CD₃OD): δ 7.09-6.91 (m, 5H), 5.30 (t, 1H, J=8.4 Hz),3.60-2.64 (m, 6H), 1.34 (s, 9H), 1.16 (t, 3H, J=7.5 Hz).

4-{(S)-2-[(S)-2-(tert-Butoxycarbonylamino)-4-methylpentanamido]-2-(4-ethylthiazol-2-yl)ethyl}phenylsulfamicacid: ¹H NMR (CD3OD) δ 7.19-7.00 (m, 4H), 5.50-5.40 (m, 1H), 4.13-4.06(m, 1H), 3.32 (1H, A of ABX,J=7.5, 18Hz), 3.12 (1H, B of ABX, J=8.1,13.8Hz), 2.79 (q, 2H, J=7.8, 14.7Hz), 1.70-1.55 (m, 1H), 1.46 (s, 9H),1.33 (t, 3H, J=2.7Hz), 0.92 (q, 6H, J=6, 10.8Hz).

4-{(S)-2-[(S)-2-(tert-Butoxycarbonylamino)-4-methylpentanamido]-2-[2-(thiophen-2-yl)thiazol-4-yl]ethyl}phenylsulfamicacid: ¹H NMR (CD3OD) δ 8.06 (d, 1H, J=84 Hz), 7.61-7.58 (m, 1H), 7.57(s, 1H), 7.15 (t, 1H, J=0.6Hz), 7.09-6.98 (m, 6H), 5.30-5.20 (m, 1H),4.10-4.00 (m, 1H), 3.19-3.13 (m, 2H), 1.63-1.55 (m, 2H), 1.48-1.33 (m,10H), 0.95-0.89 (m, 6H).

(S)-4-{2-[2-(tert-Butoxycarbonyl)acetamide]-2-(4-ethylthiazol-2-yl)ethyl}-phenylsulfamicacid: ¹H NMR (CD₃OD): δ 7.09-6.91 (m, 5H), 5.30 (t, 1H, J=8.4 Hz),3.60-2.64 (m, 6H), 1.34 (s, 9H), 1.16 (t, 3H, J=7.5 Hz).

A further embodiment of Category IV relates to inhibitors having theformula:

wherein R units and R^(5a) units further described in Table VII.

TABLE VII No. R R^(5a) G151 thiazol-2-yl hydrogen G1524-methylthiazol-2-yl hydrogen G153 4-ethylthiazol-2-yl hydrogen G1544-propylthiazol-2-yl hydrogen G155 4-iso-propylthiazol-2-yl hydrogenG156 4-cyclopropylthiazol-2-yl hydrogen G157 4-butylthiazol-2-ylhydrogen G158 4-tert-butylthiazol-2-yl hydrogen G1594-cyclohexylthiazol-2-yl hydrogen G160 4,5-dimethylthiazol-2-yl hydrogenG161 4-methyl-5-ethylthiazol-2-yl hydrogen G162 4-phenylthiazol-2-ylhydrogen G163 thiazol-2-yl (S)-iso-propyl G164 4-methylthiazol-2-yl(S)-iso-propyl G165 4-ethylthiazol-2-yl (S)-iso-propyl G1664-propylthiazol-2-yl (S)-iso-propyl G167 4-iso-propylthiazol-2-yl(S)-iso-propyl G168 4-cyclopropylthiazol-2-yl (S)-iso-propyl G1694-butylthiazol-2-yl (S)-iso-propyl G170 4-tert-butylthiazol-2-yl(S)-iso-propyl G171 4-cyclohexylthiazol-2-yl (S)-iso-propyl G1724,5-dimethylthiazol-2-yl (S)-iso-propyl G1734-methyl-5-ethylthiazol-2-yl (S)-iso-propyl G174 4-phenylthiazol-2-yl(S)-iso-propyl G175 4-(thiophen-2-yl)thiazol-2-yl (S)-iso-propyl

The compounds encompassed within this embodiment of Category IV can bemade according to the procedure outlined in Scheme V and described inExample 6 by substituting the corresponding methylcarbamate for theBoc-protected reagent. The following are non-limiting examples of thisembodiment.

4-{(S)-2-(4-Ethylthiazol-2-yl)-2-[(S)-2-(methoxycarbonylamino)-4-methylpentan-amido]ethyl}phenylsulfamicacid: ¹H NMR (CD3OD) δ 7.12-7.03 (m, 5H), 6.84 (d, 1H, J=8.4Hz), 5.40(t, 1H, J=5.7Hz), 4.16 (t, 1H, J=6.3Hz), 3.69 (s, 3H), 3.61-3.55 (m,1H), 3.29-3.27 (m, 1H), 3.14-3.07 (m, 1H), 2.81 (q, 2H, J=3.9, 11.2Hz),1.66-1.59 (m, 1H), 1.48-1.43 (m, 2H), 1.31 (t, 3H, J=4.5Hz), 0.96-0.90(m, 6H).

(S)-4-{2-(4-Ethylthiazol-2-yl)-2-[2-(methoxycarbonylamino)acetamido]ethyl}-phenylsulfamicacid: ¹H NMR (CD₃OD): δ 7.12-7.07 (m, 4H), 7.03 (s, 1H), 5.42 (t, 1H,J=5.7 Hz), 3.83-3.68 (q, 2H, J=11.4 Hz), 3.68 (s, 3H), 3.34-3.04 (m,2H), 2.83-2.76 (q, 2H, J=7.8 Hz), 1.31 (t, 3H, J=7.5 Hz).

4-{(S)-2-(4-Ethylthiazol-2-yl)-2-[(S)-2-(methoxycarbonylamino)-3-methylbutanamido]-ethyl}phenylsulfamicacid: ¹H NMR (CD₃OD) δ 8.56 (d, 1H, J=7.8Hz), 7.09 (s, 4H), 7.03 (s,1H), 5.26-5.20 (m, 1H), 3.90 (d, 1H, J=7.8Hz), 3.70 (s, 3H), 3.30 (1H, Aof ABX, obscured by solvent), 3.08 (1H, B of ABX, J=9.9, 9Hz), 2.79 (q,2H, J=11.1, 7.2Hz), 2.05-1.97 (m, 1H), 1.31 (t, 3H, J=7.5Hz), 0.88 (s,3H), 0.85 (s, 3H), 0.79-0.75 (m, 1H).

4-{(S)-2-[(S)-2-(Methoxycarbonylamino)-4-methylpentanamido]-2-[2-(thiophen-2-yl)thiazol-4-yl]ethyl}phenylsulfamicacid: ¹H NMR (CD₃OD) δ 8.22 (d, 1H, J=9Hz), 7.62-7.57 (m, H), 7.15 (t,1H, J=0.6Hz), 7.10-6.97 (m, 4H), 5.30-5.20 (m, 1H), 4.16-4.11 (m, 1H),3.67 (s, 2H), 3.22 (1H, A of ABX, J=6.9, 13.5Hz), 3.11 (1H, B of ABX,J=7.8, 13.6Hz), 1.65-1.58 (m, 1H), 1.50-1.45 (m, 2H), 0.95-0.88 (m, 6H).

Category IV of the present disclosure relates to compounds having theformula:

wherein R is a substituted or unsubstituted thiophen-2-yl orthiophen-4-yl unit and non-limiting examples of R² are further describedin Table VIII.

TABLE VIII No. R R⁸ H176 thiazol-2-yl —OC(CH₃)₃ H1774-methylthiazol-2-yl —OC(CH₃)₃ H178 4-ethylthiazol-2-yl —OC(CH₃)₃ H1794-cyclopropylthiazol-2-yl —OC(CH₃)₃ H180 4-tert-butylthiazol-2-yl—OC(CH₃)₃ H181 4-cyclohexylthiazol-2-yl —OC(CH₃)₃ H1824-(2,2,2-trifluoroethyl)thiazol-2-yl —OC(CH₃)₃ H1834-(3,3,3-trifluoropropyl)thiazol-2-yl —OC(CH₃)₃ H1844-(2,2-difluorocyclopropyl)thiazol-2-yl —OC(CH₃)₃ H1854,5-dimethylthiazol-2-yl —OC(CH₃)₃ H186 4-methyl-5-ethylthiazol-2-yl—OC(CH₃)₃ H187 4-phenylthiazol-2-yl —OC(CH₃)₃ H1884-(4-chlorophenyl)thiazol-2-yl —OC(CH₃)₃ H1894-(3,4-dimethylphenyl)thiazol-2-yl —OC(CH₃)₃ H1904-methyl-5-phenylthiazol-2-yl —OC(CH₃)₃ H1914-(thiophen-2-yl)thiazol-2-yl —OC(CH₃)₃ H192 thiazol-4-yl —OC(CH₃)₃ H1934-methylthiazol-4-yl —OC(CH₃)₃ H194 4-ethylthiazol-4-yl —OC(CH₃)₃ H1954-cyclopropylthiazol-4-yl —OC(CH₃)₃ H196 4-tert-butylthiazol-4-yl—OC(CH₃)₃ H197 4-cyclohexylthiazol-4-yl —OC(CH₃)₃ H1984-(2,2,2-trifluoroethyl)thiazol-4-yl —OC(CH₃)₃ H1994-(3,3,3-trifluoropropyl)thiazol-4-yl —OC(CH₃)₃ H2004-(2,2-difluorocyclopropyl)thiazol-4-yl —OC(CH₃)₃ H2014,5-dimethylthiazol-4-yl —OC(CH₃)₃ H202 4-methyl-5-ethylthiazol-4-yl—OC(CH₃)₃ H203 4-phenylthiazol-4-yl —OC(CH₃)₃ H2044-(4-chlorophenyl)thiazol-4-yl —OC(CH₃)₃ H2054-(3,4-dimethylphenyl)thiazol-4-yl —OC(CH₃)₃ H2064-methyl-5-phenylthiazol-4-yl —OC(CH₃)₃ H2074-(thiophen-2-yl)thiazol-4-yl —OC(CH₃)₃ H208 thiazol-2-yl —OCH₃ H2094-methylthiazol-2-yl —OCH₃ H210 4-ethylthiazol-2-yl —OCH₃ H2114-cyclopropylthiazol-2-yl —OCH₃ H212 4-tert-butylthiazol-2-yl —OCH₃ H2134-cyclohexylthiazol-2-yl —OCH₃ H214 4-(2,2,2-trifluoroethyl)thiazol-2-yl—OCH₃ H215 4-(3,3,3-trifluoropropyl)thiazol-2-yl —OCH₃ H2164-(2,2-difluorocyclopropyl)thiazol-2-yl —OCH₃ H2174,5-dimethylthiazol-2-yl —OCH₃ H218 4-methyl-5-ethylthiazol-2-yl —OCH₃H219 4-phenylthiazol-2-yl —OCH₃ H220 4-(4-chlorophenyl)thiazol-2-yl—OCH₃ H221 4-(3,4-dimethylphenyl)thiazol-2-yl —OCH₃ H2224-methyl-5-phenylthiazol-2-yl —OCH₃ H223 4-(thiophen-2-yl)thiazol-2-yl—OCH₃ H224 thiazol-4-yl —OCH₃ H225 4-methylthiazol-4-yl —OCH₃ H2264-ethylthiazol-4-yl —OCH₃ H227 4-cyclopropylthiazol-4-yl —OCH₃ H2284-tert-butylthiazol-4-yl —OCH₃ H229 4-cyclohexylthiazol-4-yl —OCH₃ H2304-(2,2,2-trifluoroethyl)thiazol-4-yl —OCH₃ H2314-(3,3,3-trifluoropropyl)thiazol-4-yl —OCH₃ H2324-(2,2-difluorocyclopropyl)thiazol-4-yl —OCH₃ H2334,5-dimethylthiazol-4-yl —OCH₃ H234 4-methyl-5-ethylthiazol-4-yl —OCH₃H235 4-phenylthiazol-4-yl —OCH₃ H236 4-(4-chlorophenyl)thiazol-4-yl—OCH₃ H237 4-(3,4-dimethylphenyl)thiazol-4-yl —OCH₃ H2384-methyl-5-phenylthiazol-4-yl —OCH₃ H239 4-(thiophen-2-yl)thiazol-4-yl—OCH₃ H240 thiazol-2-yl —CH₃ H241 4-methylthiazol-2-yl —CH₃ H2424-ethylthiazol-2-yl —CH₃ H243 4-cyclopropylthiazol-2-yl —CH₃ H2444-tert-butylthiazol-2-yl —CH₃ H245 4-cyclohexylthiazol-2-yl —CH₃ H2464-(2,2,2-trifluoroethyl)thiazol-2-yl —CH₃ H2474-(3,3,3-trifluoropropyl)thiazol-2-yl —CH₃ H2484-(2,2-difluorocyclopropyl)thiazol-2-yl —CH₃ H2494,5-dimethylthiazol-2-yl —CH₃ H250 4-methyl-5-ethylthiazol-2-yl —CH₃H251 4-phenylthiazol-2-yl —CH₃ H252 4-(4-chlorophenyl)thiazol-2-yl —CH₃H253 4-(3,4-dimethylphenyl)thiazol-2-yl —CH₃ H2544-methyl-5-phenylthiazol-2-yl —CH₃ H255 4-(thiophen-2-yl)thiazol-2-yl—CH₃ H256 thiazol-4-yl —CH₃ H257 4-methylthiazol-4-yl —CH₃ H2584-ethylthiazol-4-yl —CH₃ H259 4-cyclopropylthiazol-4-yl —CH₃ H2604-tert-butylthiazol-4-yl —CH₃ H261 4-cyclohexylthiazol-4-yl —CH₃ H2624-(2,2,2-trifluoroethyl)thiazol-4-yl —CH₃ H2634-(3,3,3-trifluoropropyl)thiazol-4-yl —CH₃ H2644-(2,2-difluorocyclopropyl)thiazol-4-yl —CH₃ H2654,5-dimethylthiazol-4-yl —CH₃ H266 4-methyl-5-ethylthiazol-4-yl —CH₃H267 4-phenylthiazol-4-yl —CH₃ H268 4-(4-chlorophenyl)thiazol-4-yl —CH₃H269 4-(3,4-dimethylphenyl)thiazol-4-yl —CH₃ H2704-methyl-5-phenylthiazol-4-yl —CH₃ H271 4-(thiophen-2-yl)thiazol-4-yl—CH₃

The compounds encompassed within Category IV of the present disclosurecan be prepared by the procedure outlined in VI and described in Example7 herein below.

EXAMPLE 7[1-(S)-(Phenylthiazol-2-yl)-2-(4-sulfoaminophenyl)ethyl]-carbamic acidtert-butyl ester (19)

Preparation of[2-(4-nitrophenyl)-1-(5)-(4-phenylthiazol-2-yl)ethyl]-carbamic acidtert-butyl ester (18): A mixture of[2-(4-nitrophenyl)-1-(S)-thiocarbamoylethyl]-carbamic acid tert-butylester, 2, (0.343 g, 1.05 mmol), 2-bromoacetophenone (0.231 g, 1.15mmol), in CH₃CN (5 mL) is refluxed 1.5 hour. The solvent is removedunder reduced pressure and the residue re-dissolved in CH₂Cl₂ thenpyridine (0.24 mL, 3.0 mmol) and Boc₂O (0.24 mL, 1.1 mmol) are added.The reaction is stirred for 2 hours and diethyl ether is added to thesolution and the precipitate which forms is removed by filtration. Theorganic layer is dried (Na₂SO₄), filtered, and concentrated to a residuewhich is purified over silica to afford 0.176 g (39%) of the desiredproduct ESI+ MS 426 (M+1).

Preparation of[1-(S)-(phenylthiazol-2-yl)-2-(4-sulfoaminophenyl)ethyl]-carbamic acidtert-butyl ester (19):[2-(4-nitrophenyl)-1-(S)-(4-phenylthiazol-2-yl)ethyl]-carbamic acidtert-butyl ester, 18, (0.176 g, 0.41 mmol) is dissolved in MeOH (4 mL).A catalytic amount of Pd/C (10% w/w) is added and the mixture is stirredunder a hydrogen atmosphere 12 hours. The reaction mixture is filteredthrough a bed of CELITE™ and the solvent is removed under reducedpressure. The crude product is dissolved in pyridine (12 mL) and treatedwith SO₃-pyridine (0.195 g, 1.23 mmol). The reaction is stirred at roomtemperature for 5 minutes after which a 7% solution of NH₄OH (10 mL) isadded. The mixture is then concentrated and the resulting residue ispurified by reverse phase chromatography to afford 0.080 g of thedesired product as the ammonium salt. ¹H NMR (300 MHz, MeOH-d₄) δ 7.93(d, J=6.0 Hz, 2H), 7.68 (s, 1H), 7.46-7.42 (m, 3H), 7.37-7.32 (m, 1H),7.14-7.18 (m, 3H), 5.13-5.18 (m, 1H), 3.40 (dd, J=4.5 and 15.0 Hz, 1H),3.04 (dd, J=9.6 and 14.1 Hz, 1H), 1.43 (s, 9H).

The following are further non-limiting examples of Category IV of thepresent disclosure.

(S)-4-(2-(4-Methylthiazol-2-yl)-2-pivalamidoethyl)phenylsulfamic acid:¹H NMR(CD₃OD): δ 7.31 (s, 4H), 7.20 (s, 1H), 5.61-5.56 (m, 1H),3.57-3.22 (m, 2H), 2.62 (s, 3H) 1.31 (s, 3H).

(S)-4-(2-(4-Ethylthiazol-2-yl)-2-pivalamidoethyl)phenylsulfamic acid: ¹HNMR (300 MHz, MeOH-d₄) δ 7.92 (d, J=8.1 Hz, 1H), 7.12-7.14 (m, 4H), 7.03(s, 1H), 5.38-5.46 (m, 1H), 3.3-3.4 (m, 1H), 3.08 (dd, J=10.2 and 13.8Hz, 1H), 2.79 (q, J=7.2 Hz, 2H), 1.30 (t, J=7.2 Hz, 3H), 1.13 (s, 9H).

(S)-4-(2-(4-(Hydroxymethyl)thiazol-2-yl)-2-pivalamidoethyl)phenylsulfamicacid: ¹H NMR (300 MHz, MeOH-d₄) δ 7.92 (d, J=8.1 Hz, 1H), 7.24 (s, 1H),7.08 (d, J=8.7 Hz, 2H), 7.00 (d, J=8.7 Hz, 2H), 5.29-5.37 (m, 1H), 4.55(s, 2H), 3.30 (dd, J=4.8 and 13.5 Hz, 1H), 2.99 (dd, J=10.5 and 13.5 Hz,1H), 0.93 (s, 9H).

(S)-4-(2-(4-(Ethoxycarbonyl)thiazol-2-yl)-2-pivalamidoethyl)phenylsulfamicacid: ¹H NMR (300 MHz, MeOH-d₄) δ 8.30 (s, 1H), 8.04 (d, J=8.1 Hz, 1H),7.13 (s, 4H), 5.41-5.49 (m, 1H), 4.41 (q, J=7.2 Hz, 2H), 3.43 (dd, J=5.1and 13.8 Hz, 1H), 3.14 (dd, J=5.7 and 9.9 Hz, 1H), 1.42 (t, J=7.2 Hz,3H), 1.14 (s, 9H).

(S)-4-(2-(4-Phenylthiazol-2-yl)-2-pivalamidoethyl)phenylsulfamic acid:¹H NMR (300 MHz, MeOH-d₄) δ 7.94-8.01 (m, 3H), 7.70 (s, 1H), 7.42-7.47(m, 2H), 7.32-7.47 (m, 1H), 7.13-7.20 (m, 3H), 5.48-5.55 (m, 1H), 3.50(dd, J=5.1 and 14.1 Hz, 1H), 3.18 (dd, J=10.2 and 14.1 Hz, 1H), 1.17 (s,9H).

4-((S)-2-(4-(3-Methoxyphenyl)thiazol-2-yl)-2-pivalamidoethyl)phenylsulfamicacid: ¹H NMR (CD₃OD): δ 7.96-7.93 (d, 1H, J=8.1 Hz), 7.69 (s, 1H),7.51-7.49 (d, 2H, J=7.9 Hz), 7.33 (t, 1H, J=8.0 Hz), 7.14 (s, 4H),6.92-6.90 (d, 1H, J=7.8 Hz), 5.50 (t, 1H, J=5.1 Hz), 3.87 (s, 3H),3.50-3.13 (m, 2H), 1.15 (s, 9H).

4-((S)-2-(4-(2,4-Dimethoxyphenyl)thiazol-2-yl)-2-pivalamidoethyl)phenylsulfamicacid: ¹H NMR (CD₃OD): δ 8.11-8.09 (d, 1H, J=7.8 Hz), 7.96-7.93 (d, 1H,J=8.4 Hz), 7.74 (s, 1H), 7.18-7.16 (m, 4H), 6.67-6.64 (d, 2H, J=9.0 Hz),5.55-5.47 (m, 1H), 3.95 (s, 3H), 3.87 (s, 3H), 3.52-3.13 (m, 2H), 1.17(s, 9H).

(S)-4-(2-(4-Benzylthiazol-2-yl)-2-pivalamidoethyl)phenylsulfamic acid:¹H NMR (CD₃OD) δ 7.85 (d, 1H, J=8.4Hz), 7.38-7.20 (m, 4H), 7.11-7.02 (m,1H), 7.00 (s, 1H), 5.42-5.37 (m, 1H), 4.13 (s, 2H), 3.13-3.08 (m, 2H),1.13 (s, 9H).

(S)-4-(2-Pivalamido-2-(4-(thiophen-2-ylmethyl)thiazol-2-yl)ethyl)phenylsulfamicacid: ¹H NMR (CD₃OD) δ 7.88-7.85 (d, 1H), 7.38-7.35 (m, 1H), 7.10-7.01(m, 4H), 7.02 (s, 1H), 5.45-5.38 (m, 1H), 4.13 (s, 2H), 3.13-3.05 (m,2H), 1.13 (2, 9H).

(S)-4-(2-(4-(3-Methoxybenzyl)thiazol-2-yl)-2-pivalamidoethyl)phenylsulfamicacid: ¹H NMR (CD₃OD) δ 7.85 (d, 1H, J=8.4Hz), 7.25-7.20 (m, 1H),7.11-7.02 (m, 4H), 7.01 (s, 1H), 6.90-6.79 (m, 2H), 5.45-5.40 (m, 1H),4.09 (s, 2H), 3.79 (s, 3H), 3.12-3.08 (m, 2H), 1.10 (s, 9H).

4-((S)-2-(4-(2,3-Dihydrobenzo[b][1,4]dioxin-6-yl)thiazol-2-yl)-2-pivalamidoethyl)-phenylsulfamicacid: ¹H NMR (CD₃OD): δ 7.53 (s, 1H), 7.45 (s, 1H), 7.42-7.40 (d, 1H,J=8.4 Hz), 7.19-7.15 (m, 4H), 6.91-6.88 (d, 2H, J=8.4 Hz), 5.51-5.46 (m,1H), 4.30 (s, 4H), 3.51-3.12 (m, 2H), 1.16 (s, 9H).

(S)-4-(2-(5-Methyl-4-phenylthiazol-2-yl)-2-pivalamidoethyl)phenylsulfamicacid: ¹H NMR (CD₃OD): δ 7.63-7.60 (d, 2H, J=7.1 Hz), 7.49-7.35 (m, 3H),7.14 (s, 4H), 5.43-5.38 (m, 1H), 3.42-3.09 (m, 2H), 2.49 (s, 3H), 1.14(s, 9H).

(S)-4-(2-(4-(Biphen-4-yl)thiazol-2-yl)-2-pivalamidoethyl)phenylsulfamicacid: ¹H NMR (CD₃OD): δ 8.04-8.01 (m, 2H), 7.72-7.66 (m, 5H), 7.48-7.35(m, 3H), 7.15 (s, 4H), 5.50 (t, 1H, J=5.0 Hz), 3.57-3.15 (d, 2H), 1.16(s, 9H).

(S)-4-(2-tert-Butoxycarbonyl-2-(2-methylthaizol-4-yl)-phenylsulfamicacid ¹H NMR (300 MHz, D₂O) δ 6.99-7.002 (m, 4H), 6.82 (s, 1H), 2.26 (dd,J=13.8 and 7.2 Hz, 1H), 2.76 (dd, J=13.8 and 7.2 Hz, 1H), 2.48 (s, 3H),1.17 (s, 9H).

(S)-4-(2-(tert-Butoxycarbonyl)-2-(4-propylthiazol-2-yl)ethyl)-phenylsulfamic acid: ¹H NMR (300 MHz, CD₃OD): δ 7.18-7.02 (m, 5H), 5.06-5.03(m, 1H), 3.26 (dd, J=13.8, 4.8 Hz, 1H), 2.95 (dd, J=13.8, 9.3 Hz, 1H),2.74 (dd, J=15.0, 7.2 Hz, 2H), 1.81-1.71 (m, 2H), 1.40 (s, 7H), 1.33(bs, 2H), 0.988 (t, J=7.5 Hz 3H).

(S)-4-(2-(tert-Butoxycarbonyl)-2-(4-tert-butylthiazol-2-yl)ethyl)-phenylsulfamic acid: ¹H NMR (300 MHz, CD₃OD): δ 7.12 (s, 4H), 7.01 (s, 1H),5.11-5.06 (m, 1H), 3.32-3.25 (m, 1H), 2.96 (m, 1H), 1.42 (s, 8H), 1.38(s, 9H), 1.32 (s, 1H).

(S)-4-(2-(tert-Butoxycarbonylamino)-2-(4-(methoxymethyl)thiazol-2-yl)ethyl)-phenylsulfamic acid: ¹H NMR (300 MHz, CD₃OD): δ 7.36 (s, 1H), 7.14-7.05 (m,4H), 5.06 (dd, J=9.0, 5.1 Hz, 1H), 4.55 (s, 2H), 3.42 (s, 3H), 3.31-3.24(m, 1H), 2.97 (dd, J=13.8, 9.9 Hz, 1H), 1.47-1.31 (m, 9H).

(S)-4-(2-tert-Butoxycarbonylamino)-2-(4-(2-hydroxymethyl)thiazol-2-yl)ethyl)phenylsulfamicacid: ¹H NMR (300 MHz, MeOH-d₄) δ 7.22-7.25 (m, 1H), 7.09-7.15 (m, 4H),5.00-5.09 (m, 1H), 4.32-4.35 (m, 1H), 3.87 (t, J=6.6 Hz, 2H), 3.23-3.29(m, 1H), 3.09-3.18 (m, 1H), 2.98 (t, J=6.6 Hz, 2H), 1.41 (s, 9H).

(S)-4-(2-tert-Butoxycarbonylamino)-2-(4-(2-ethoxy-2-oxoethyl)-thiazole-2-yl)-ethyl)phenylsulfamicacid: ¹H NMR (300 MHz, MeOH-d₄) δ 7.29 (s, 1H), 7.09-7.16 (m, 4H),5.04-5.09 (m, 1H), 4.20 (q, J=6.9 Hz, 2H), 3.84 (s, 2H), 3.30 (dd, J=4.8and 14.1 HZ, 1H), 2.97 (dd, J=9.6 Hz and 13.8 Hz, 1H), 1.41 (s, 9H),1.29 (t, J=7.2 Hz, 3H).

(S)-4-(2-(tert-Butoxycarbonylamino)-2-(4-(2-methoxy-2-oxoethyl)thiazol-2-yl)ethyl)phenylsulfamicacid: ¹H NMR (300 MHz, MeOH-d₄) δ 7.31 (s, 1H), 7.01-7.16 (m, 4H),5.04-5.09 (m, 1H), 4.01 (s, 2H), 3.78 (s, 2H), 3.74 (s, 3H), 3.29 (dd,J=5.1 and 13.8 Hz, 1H), 2.99 (dd, J=9.3 and 13.8 Hz, 1H), 1.41 (s, 9H).

(S)-4-(2-(tert-Butoxycarbonylamino)-2-(2-(pivaloyloxy)thiazol-4-yl)ethyl)-phenylsulfamicacid: ¹H NMR (300 MHz, D₂O) δ 6.95 (s, 4H), 6.63 (s, 1H), 2.94 (dd,J=13.5 and 4.8 Hz, 1H), 2.75 (dd, J=13.5 and 4.8 Hz, 1H), 1.16 (s, 9H),1.13 (s, 9H).

(S)-4-(2-(tert-Butoxycarbonylamino)-2-(5-phenylthiazol-2-yl)ethyl)-phenylsulfamic acid: ¹H NMR (300 MHz, CD₃OD): δ 7.98 (s, 1H), 7.62 (d, J=7.2Hz, 2H), 7.46-7.35 (m, 4H), 7.14 (s, 4H), 5.09 (bs, 1H), 3.07-2.99 (m,2H), 1.43 (s, 9H).

4-((S)-2-(tert-Butoxycarbonylamino)-2-(4-(3-(trifluoromethyl)phenyl)thiazol-2-yl)ethyl)phenylsulfamic acid: ¹H NMR (300 MHz, CD₃OD): δ 8.28 (s, 1H), 8.22-8.19 (m,1H), 7.89 (s, 1H), 7.65 (d, J=5.1 Hz, 2H), 7.45 (d, J=8.1 Hz, 1H), 7.15(s, 4H), 5.17-5.14 (m, 1H), 3.43-3.32 (m, 1H), 3.05 (dd, J=14.1, 9.6 Hz,1H), 1.42 (s, 9H).

(S)-4-(2-(tert-Butoxycarbonylamino)-2-(4-phenylthiazol-2-yl)ethyl)-phenylsulfamic acid: ¹H NMR (300 MHz, CD₃OD): δ 7.98 (s, 1H), 7.94 (d, J=7.2Hz, 2H), 7.46-7.35 (m, 4H), 7.14 (s, 4H), 5.09 (bs, 1H), 3.07-2.99 (m,2H), 1.43 (s, 9H).

(S,S)-2-(2-{2-[2-tert-Butoxycarbonylamino-2-(4-sulfoaminophenyl)ethyl]thiazol-4-yl}acetylamido)-3-phenylpropionicacid methyl ester: ¹H NMR (300 MHz, MeOH-d₄) δ 6.85-6.94 (m, 9H), 6.64(s, 1H), 4.83 (s, 1H), 4.54-4.58 (m, 1H), 3.49 (s, 3H), 3.39 (s, 2H),2.80-2.97 (m, 1H), 2.64-2.78 (m, 1H), 1.12 (s, 9H).

(S)-[1-{1-Oxo-4-[2-(1-phenyl-1H-tetrazol-5-sulfonyl)ethyl]-1H-1λ⁴-thiazol-2-yl}-2-(4-sulfamino-phenyl)-ethyl]-carbamicacid tert-butyl ester: ¹H NMR (300 MHz, MeOH-d₄) δ 7.22-7.75 (m, 2H),7.62-7.69 (m, 2H), 7.55 (s, 1H), 7.10-7.20 (m, 5H), 5.25 (m, 1H),4.27-4.36 (m, 1H), 4.11-4.21 (m, 1H), 3.33-3.44 (m, 4H), 2.84-2.90 (m,1H), 1.33 (s, 9H).

4-((S)-2-(tert-Butoxycarbonylamino)-2-(4-(thiophen-3-yl)thiazol-2-yl)ethyl)phenylsulfamic acid: ¹H NMR (300 MHz, CD₃OD): δ 7.84 (dd, J=3.0, 1.5 Hz, 1H),7.57-7.55 (m, 2H), 7.47 (dd, J=4.8, 3.0 Hz, 1H), 7.15 (s, 4H), 5.15-5.10(m, 1H), 3.39-3.34 (m, 1H), 3.01 (dd, J=14.1, 9.6 Hz, 1H), 1.42 (s, 8H),1.32 (s, 1H).

(S)-4-(2-(Benzo[d]thiazol-2-ylamino)-2-(tert-butoxycarbonyl)ethyl)phenylsulfamicacid: ¹H NMR (CD₃OD) δ 7.86-7.82 (m, 2H), 7.42 (t, 2H, J=7.1 Hz), 7.33(t, 1H, J=8.2 Hz), 7.02 (s, 4H), 5.10-5.05 (m, 1H), 2.99-2.91 (m, 2H),1.29 (s, 9H).

(S)-4-(2-tert-Butoxycarbonylamino)-2-(2-methylthiazol-4-yl)-phenylsulfamicacid ¹H NMR (300 MHz, D₂O) δ 6.99-7.002 (m, 4H), 6.82 (s, 1H), 2.26 (dd,J=13.8 and 7.2 Hz, 1H), 2.76 (dd, J=13.8 and 7.2 Hz, 1H), 2.48 (s, 3H),1.17 (s, 9H).

The first aspect of Category V of the present disclosure relates to2-(thiazol-2-yl) compounds having the formula:

wherein R¹, R², R³, and L are further defined herein in Table IX hereinbelow.

TABLE IX No. L R¹ R² R³ I272 —C(O)CH₂— phenyl —CH₃ —H I273 —C(O)CH₂—2-fluorophenyl —CH₃ —H I274 —C(O)CH₂— 3-fluorophenyl —CH₃ —H I275—C(O)CH₂— 4-fluorophenyl —CH₃ —H I276 —C(O)CH₂— 2,3-difluorophenyl —CH₃—H I277 —C(O)CH₂— 3,4-difluorophenyl —CH₃ —H I278 —C(O)CH₂—3,5-difluorophenyl —CH₃ —H I279 —C(O)CH₂— 2-chlorophenyl —CH₃ —H I280—C(O)CH₂— 3-chlorophenyl —CH₃ —H I281 —C(O)CH₂— 4-chlorophenyl —CH₃ —HI282 —C(O)CH₂— 2,3-dichlorophenyl —CH₃ —H I283 —C(O)CH₂—3,4-dichlorophenyl —CH₃ —H I284 —C(O)CH₂— 3,5-dichlorophenyl —CH₃ —HI285 —C(O)CH₂— 2-hydroxyphenyl —CH₃ —H I286 —C(O)CH₂— 3-hydroxyphenyl—CH₃ —H I287 —C(O)CH₂— 4-hydroxyphenyl —CH₃ —H I288 —C(O)CH₂—2-methoxyphenyl —CH₃ —H I289 —C(O)CH₂— 3-methoxyphenyl —CH₃ —H I290—C(O)CH₂— 4-methoxyphenyl —CH₃ —H I291 —C(O)CH₂— 2,3-dimethoxyphenyl—CH₃ —H I292 —C(O)CH₂— 3,4-dimethoxyphenyl —CH₃ —H I293 —C(O)CH₂—3,5-dimethoxyphenyl —CH₃ —H I294 —C(O)CH₂— phenyl —CH₂CH₃ —H I295—C(O)CH₂— 2-fluorophenyl —CH₂CH₃ —H I296 —C(O)CH₂— 3-fluorophenyl—CH₂CH₃ —H I297 —C(O)CH₂— 4-fluorophenyl —CH₂CH₃ —H I298 —C(O)CH₂—2,3-difluorophenyl —CH₂CH₃ —H I299 —C(O)CH₂— 3,4-difluorophenyl —CH₂CH₃—H I300 —C(O)CH₂— 3,5-difluorophenyl —CH₂CH₃ —H I301 —C(O)CH₂—2-chlorophenyl —CH₂CH₃ —H I302 —C(O)CH₂— 3-chlorophenyl —CH₂CH₃ —H I303—C(O)CH₂— 4-chlorophenyl —CH₂CH₃ —H I304 —C(O)CH₂— 2,3-dichlorophenyl—CH₂CH₃ —H I305 —C(O)CH₂— 3,4-dichlorophenyl —CH₂CH₃ —H I306 —C(O)CH₂—3,5-dichlorophenyl —CH₂CH₃ —H I307 —C(O)CH₂— 2-hydroxyphenyl —CH₂CH₃ —HI308 —C(O)CH₂— 3-hydroxyphenyl —CH₂CH₃ —H I309 —C(O)CH₂— 4-hydroxyphenyl—CH₂CH₃ —H I310 —C(O)CH₂— 2-methoxyphenyl —CH₂CH₃ —H I311 —C(O)CH₂—3-methoxyphenyl —CH₂CH₃ —H I312 —C(O)CH₂— 4-methoxyphenyl —CH₂CH₃ —HI313 —C(O)CH₂— 2,3-dimethoxyphenyl —CH₂CH₃ —H I314 —C(O)CH₂—3,4-dimethoxyphenyl —CH₂CH₃ —H I315 —C(O)CH₂— 3,5-dimethoxyphenyl—CH₂CH₃ —H I316 —C(O)CH₂CH₂— phenyl —CH₃ —H I317 —C(O)CH₂CH₂—2-fluorophenyl —CH₃ —H I318 —C(O)CH₂CH₂— 3-fluorophenyl —CH₃ —H I319—C(O)CH₂CH₂— 4-fluorophenyl —CH₃ —H I320 —C(O)CH₂CH₂— 2,3-difluorophenyl—CH₃ —H I321 —C(O)CH₂CH₂— 3,4-difluorophenyl —CH₃ —H I322 —C(O)CH₂CH₂—3,5-difluorophenyl —CH₃ —H I323 —C(O)CH₂CH₂— 2-chlorophenyl —CH₃ —H I324—C(O)CH₂CH₂— 3-chlorophenyl —CH₃ —H I325 —C(O)CH₂CH₂— 4-chlorophenyl—CH₃ —H I326 —C(O)CH₂CH₂— 2,3-dichlorophenyl —CH₃ —H I327 —C(O)CH₂CH₂—3,4-dichlorophenyl —CH₃ —H I328 —C(O)CH₂CH₂— 3,5-dichlorophenyl —CH₃ —HI329 —C(O)CH₂CH₂— 2-hydroxyphenyl —CH₃ —H I330 —C(O)CH₂CH₂—3-hydroxyphenyl —CH₃ —H I331 —C(O)CH₂CH₂— 4-hydroxyphenyl —CH₃ —H I332—C(O)CH₂CH₂— 2-methoxyphenyl —CH₃ —H I333 —C(O)CH₂CH₂— 3-methoxyphenyl—CH₃ —H I334 —C(O)CH₂CH₂— 4-methoxyphenyl —CH₃ —H I335 —C(O)CH₂CH₂—2,3-dimethoxyphenyl —CH₃ —H I336 —C(O)CH₂CH₂— 3,4-dimethoxyphenyl —CH₃—H I337 —C(O)CH₂CH₂— 3,5-dimethoxyphenyl —CH₃ —H I338 —C(O)CH₂CH₂—phenyl —CH₂CH₃ —H I339 —C(O)CH₂CH₂— 2-fluorophenyl —CH₂CH₃ —H I340—C(O)CH₂CH₂— 3-fluorophenyl —CH₂CH₃ —H I341 —C(O)CH₂CH₂— 4-fluorophenyl—CH₂CH₃ —H I342 —C(O)CH₂CH₂— 2,3-difluorophenyl —CH₂CH₃ —H I343—C(O)CH₂CH₂— 3,4-difluorophenyl —CH₂CH₃ —H I344 —C(O)CH₂CH₂—3,5-difluorophenyl —CH₂CH₃ —H I345 —C(O)CH₂CH₂— 2-chlorophenyl —CH₂CH₃—H I346 —C(O)CH₂CH₂— 3-chlorophenyl —CH₂CH₃ —H I347 —C(O)CH₂CH₂—4-chlorophenyl —CH₂CH₃ —H I348 —C(O)CH₂CH₂— 2,3-dichlorophenyl —CH₂CH₃—H I349 —C(O)CH₂CH₂— 3,4-dichlorophenyl —CH₂CH₃ —H I350 —C(O)CH₂CH₂—3,5-dichlorophenyl —CH₂CH₃ —H I351 —C(O)CH₂CH₂— 2-hydroxyphenyl —CH₂CH₃—H I352 —C(O)CH₂CH₂— 3-hydroxyphenyl —CH₂CH₃ —H I353 —C(O)CH₂CH₂—4-hydroxyphenyl —CH₂CH₃ —H I354 —C(O)CH₂CH₂— 2-methoxyphenyl —CH₂CH₃ —HI355 —C(O)CH₂CH₂— 3-methoxyphenyl —CH₂CH₃ —H I356 —C(O)CH₂CH₂—4-methoxyphenyl —CH₂CH₃ —H I357 —C(O)CH₂CH₂— 2,3-dimethoxyphenyl —CH₂CH₃—H I358 —C(O)CH₂CH₂— 3,4-dimethoxyphenyl —CH₂CH₃ —H I359 —C(O)CH₂CH₂—3,5-dimethoxyphenyl —CH₂CH₃ —H

The compounds encompassed within the first aspect of Category V of thepresent disclosure can be prepared by the procedure outlined in SchemeVII and described in Example 8 herein below.

EXAMPLE 8{4-[2-(S)-(4-Ethylthiazol-2-yl)-2-(2-phenylacetylamido)ethyl]phenyl}sulfamicacid (21)

Preparation ofN-[1-(4-ethylthiazol-2-yl)-2-(4-nitrophenyl)ethyl]-2-phenyl-acetamide(20): To a solution of1-(S)-(4-ethylthiazol-2-yl)-2-(4-nitrophenyl)ethyl amine hydrobromide,3, (0.393 g, 1.1 mmol), phenylacetic acid (0.190 g, 1.4 mmol) and1-hydroxybenzotriazole (HOBt) (0.094 g, 0.70 mmol) in DMF (10 mL) at 0°,is added 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide (EDCI) (0.268 g,1.4 mmol) followed by triethylamine (0.60 mL, 4.2 mmol). The mixture isstirred at 0° C. for 30 minutes then at room temperature overnight. Thereaction mixture is diluted with water and extracted with EtOAc. Thecombined organic phase is washed with 1 N aqueous HCl, 5% aqueousNaHCO₃, water and brine, and dried over Na₂SO₄. The solvent is removedin vacuo to afford 0.260 g (60% yield) of the desired product which isused without further purification. ESI+ MS 396 (M+1).

Preparation of{4-[2-(S)-(4-ethylthiazol-2-yl)-2-(2-phenylacetylamido)ethyl]-phenyl}sulfamicacid (21):N-[1-(4-ethylthiazol-2-yl)-2-(4-nitrophenyl)ethyl]-2-phenyl-acetamide,20, (0.260 g) is dissolved in MeOH (4 mL). A catalytic amount of Pd/C(10% w/w) is added and the mixture is stirred under a hydrogenatmosphere 18 hours. The reaction mixture is filtered through a bed ofCELITE™ and the solvent is removed under reduced pressure. The crudeproduct is dissolved in pyridine (12 mL) and treated with SO₃-pyridine(0.177 g, 1.23). The reaction is stirred at room temperature for 5minutes after which a 7% solution of NH₄OH (10 mL) is added. The mixtureis then concentrated and the resulting residue is purified by reversephase chromatography to afford 0.136 g of the desired product as theammonium salt. ¹H NMR (CD₃OD) δ 8.60 (d, 1H, J=8.1 Hz), 7.33-7.23 (m,3H), 7.16-7.00 (m, 6H), 5.44-5.41 (m, 1H), 3.28 (1H, A of ABX, obscuredby solvent), 3.03 (1H, B of ABX, J=14.1, 9.6Hz), 2.80 (q, 2H, J=10.5,7.8Hz) 1.31 (t, 3H, J=4.6Hz).

The following are non-limiting examples of the first aspect of CategoryV of the present disclosure.

(S)-4-(2-(4-Ethylthiazol-2-yl)-2-(2-(2-fluorophenyl)acetamido)ethyl)phenylsulfamicacid: ¹H NMR (CD₃OD) δ 8.65 (d, 1H, J=8.4Hz), 7.29-7.15 (m, 1H),7.13-7.03 (m, 7H), 5.46-5.42 (m, 1H), 3.64-3.51 (m, 2H), 3.29 (1H), 3.04(1H, B of ABX, J=13.8, 9.6Hz), 2.81 (q, 2H, J=15.6, 3.9Hz), 1.31 (t, 3H,J=7.8Hz). ¹⁹F NMR (CD₃OD) δ 43.64.

(S)-4-(2-(4-Ethylthiazol-2-yl)-2-(2-(3-fluorophenyl)acetamido)ethyl)phenylsulfamicacid: ¹H NMR (CD3OD) δ 8.74 (d, 1H, J=8.4Hz), 7.32 (q, 1H, J=6.6,14.2Hz), 7.10-6.91 (m, 8H), 5.47-5.40 (m, 1H), 3.53 (s, 2H), 3.30 (1H),3.11 (1H, B of ABX, J=9.6, 14.1Hz), 2.80 (q, 2H, J=6.6, 15.1Hz), 1.31(t, 3H, J=7.8Hz). 19F NMR δ 47.42.

(S)-4-(2-(2-(2,3-Difluorophenyl)acetamido)-2-(4-ethylthiazol-2-yl)ethyl)-phenylsulfamicacid: ¹H NMR (CD₃OD) δ 7.16-7.05 (m, 5H), 6.85-6.80 (m, 1H), 5.48-5.43(m, 1H), 3.63 (s, 2H), 3.38 (1H, A of ABX, obscured by solvent), 3.03(1H), 2.80 (q, H, J=15.1, 7.8Hz), 1.31 (t, 3H, J=7.5Hz).

(S)-4-(2-(2-(3,4-Difluorophenyl)acetamido)-2-(4-ethylthiazol-2-yl)ethyl)-phenylsulfamicacid: ¹H NMR (CD₃OD) δ 8.75 (d, 1H, J=7.8Hz), 7.23-7.04 (m, 6H),6.88-6.84 (m, 1H), 5.44-5.40 (m, 1H), 3.49 (s, 2H), 3.34 (1H), 3.02 (1H,B of ABX, J=14.1, 9.9Hz), 2.80 (q, 2H, J=15.1, 7.8Hz), 1.31 (t, 1H,J=7.5Hz). 19F NMR (CD3OD) δ 22.18, 19.45.

(S)-4-(2-(2-(2-Chlorophenyl)acetamido)-2-(4-ethylthiazol-2-yl)ethyl)phenylsulfamicacid: ¹H NMR (CD3OD) δ 7.39-7.36 (m, 1H), 7.27-7.21 (m, 2H), 7.15-6.98(m, 5H), 5.49-5.44 (m, 1H), 3.69 (d, 2H, J=11.7 Hz), 3.32 (1H), 3.04(1H, B of ABX, J=9.3, 13.9 Hz), 2.80 (q, 2H, J=7.8, 15.3 Hz), 1.31 (t,3H, J=7.5 Hz).

(S)-4-(2-(2-(3-Chlorophenyl)acetamido)-2-(4-ethylthiazol-2-yl)ethyl)phenylsulfamicacid: ¹H NMR (CD3OD) δ 7.33-7.23 (m, 3H), 7.13-7.03 (m, 5H), 5.43 (q,1H, J=5.1, 9.6Hz), 3.51 (s, 2H), 3.29 (1H), 3.03 (1H, B of ABX, J=9.9,14.1Hz), 2.80 (q, 2H, J=7.5, 15Hz), 1.31 (t, 3H, J=7.8Hz).

(S)-4-(2-(4-Ethylthiazol-2-yl)-2-(2-(3-hydroxyphenyl)acetamido)ethyl)-phenylsulfamicacid: ¹H NMR (CD₃OD) δ 7.16-7.08 (m, 3H), 7.03-7.00 (m, 3H), 6.70-6.63(m, 2H), 5.42-5.40 (m, 1H), 3.44 (s, 2H), 3.28 (1H, A of ABX, obscuredby solvent), 3.04 (B of ABX, J=14.1, 9.6Hz), 2.89 (q, 2H, J=15, 7.5Hz),1.31 (t, 3H, J=7.5Hz).

(S)-4-(2-(4-Ethylthiazol-2-yl)-2-(2-(2-methoxyphenyl)acetamido)ethyl)-phenylsulfamicacid: ¹H NMR (CD₃OD) δ 8.00 (d, 1H, J=7.8Hz), 7.26 (t, 1H, J=13.2Hz),7.09-7.05 (m, 4H), 7.01 (s, 1H), 6.91-6.89 (m, 4H), 5.44-5.39 (m, 1H),3.71 (s, 3H), 3.52 (s, 2H), 3.26 (1H, A of ABX, J=14.1, 5.1Hz), 3.06 (1HB of ABX, J=13.8, 8.4Hz), 2.80 (q, 2H, J=8.1, 15.6Hz), 1.31 (t, 3H,J=1.2Hz).

(S)-4-{2-(4-Ethylthiazol-2-yl)-2-[2-(3-methoxyphenyl)acetamido]ethyl}-phenylsulfamicacid: ¹H NMR (CD₃OD) δ 8.58 (d, 1H, J=8.1 Hz), 7.21 (t, 1H, J=7.8Hz),7.12-7.02 (m, 4H), 6.81 (s, 2H), 6.72 (d, 1H, J=7.5Hz), 5.45-5.40 (m,1H), 3.79 (s, 3H), 3.50 (s, 2H), 3.29 (1H, A of ABX, obscured bysolvent), 3.08 (1H, B of ABX, J=11.8, 5.1Hz), 2.80 (q, 2H, J=15, 7.5Hz),1.31 (t, 3H, J=6.6Hz).

(S)-4-(2-(4-Ethylthiazol-2-yl)-2-(3-phenylpropanamido)ethyl)phenylsulfamicacid: ¹H NMR (CD₃OD) δ 8.56 (d, 1H, J=8.4Hz), 7.25-6.98 (m, 9H),5.43-5.38 (m, 1H), 3.26 (1H, A of ABX, J=14.1, 9.6Hz), 2.97 (1H, B ofABX, J=10.9, 3Hz), 2.58-2.76 (m, 3H), 2.98 (q, 2H, J=13.8, 7.2Hz), 1.29(t, 3H, J=8.7Hz).

(S)-4-(2-(2-(3,4-Dimethoxyphenyl)acetamido)-2-(4-ethylthiazol-2-yl)ethyl)-phenylsulfamicacid: ¹H NMR (CD₃OD) δ 7.12-7.03 (m, 3H), 6.91 (d, 1H, J=8.4Hz), 6.82(s, 1H), 6.66 (d, 1H, J=2.1Hz), 6.63 (d, 1H, J=2.1Hz), 5.43 (m, 1H),3.84 (s, 3H), 3.80 (s, 3H), 3.45 (s, 2H), 3.30 (1H), 3.03 (1H, B of ABX,J=14.1, 9.6Hz), 2.79 (q, 2H, J=15.1, 7.2Hz), 1.30 (t, 3H, J=7.2Hz).

(S)-4-(2-(2-(2,3-Dimethoxyphenyl)acetamido)-2-(4-ethylthiazol-2-yl)ethyl)-phenylsulfamicacid: ¹H NMR (CD₃OD) δ 8.31 (d, 1H, J=7.8Hz), 7.11-6.93 (m, 6H), 6.68(d, 1H, J=7.5Hz), 5.49-5.40 (m, 1H), 3.87 (s, 3H), 3.70 (s, 3H), 3.55(s, 2H), 3.26 (1H, A of ABX, obscured by solvent), 3.06 (1H, B of ABX,J=13.9, 9Hz), 2.80 (q, 2H, J=14.8, 7.5Hz), 1.31 (t, 3H, J=7.5Hz).

(S)-4-(2-(3-(3-Chlorophenyl)propanamido)-2-(4-ethylthiazol-2-yl)ethyl)phenyl-sulfamicacid: ¹H NMR (CD3OD) δ 7.27-7.18 (m, 3H), 7.13-7.08 (m, 5H), 7.01 (s,1H), 5.39 (q, 1H, J=5.1, 9.4Hz), 3.28 (1H, A of ABX, J=5.1, 14.1Hz),2.97 (1H, B of ABX, J=9.3, 13.9Hz), 2.88-2.76 (m, 4H), 2.50 (t, 2H,J=8.1Hz), 1.31 (t, 3H, J=7.8Hz).

(S)-4-(2-(4-Ethylthiazol-2-yl)-2-(3-(2-methoxyphenyl)propanamido)ethyl)-phenylsulfamicacid: ¹H NMR (CD₃OD) δ 7.18-7.08 (m, 6H), 6.92 (d, 1H, J=8.1Hz), 6.82(t, 1H, J=7.5Hz), 5.40-5.35 (m, 1H), 3.25 (1H, A of ABX, J=15, 5.4Hz),3.00 (1H, B of ABX, J=10.5, 7.5Hz), 2.88-2.76 (m, 4H), 2.47 (q, 2H,J=9.1, 6Hz), 1.31 (t, 3H, J=7.8Hz).

(S)-4-(2-(4-Ethylthiazol-2-yl)-2-(3-(3-methoxyphenyl)propanamido)ethyl)-phenylsulfamicacid: ¹H NMR (CD₃OD) δ 7.19-7.00 (m, 5H), 6.75 (s, 1H), 6.73 (s, 1H),5.42-5.37 (m, 1H), 3.76 (s, 3H), 3.25 (1H, A of ABX, J=13.9, 5.4Hz),2.98 (1H, B of ABX, J=14.1, 9.6Hz), 2.86-2.75 (m, 4H), 2.48 (q, 2H,J=11.7, 1.2Hz), 1.31 (t, 3H, J=7.5Hz).

(S)-4-(2-(4-Ethylthiazol-2-yl)-2-(3-(4-methoxyphenyl)propanamido)ethyl)-phenylsulfamicacid: ¹H NMR (CD₃OD) δ 7.13-6.99 (m, 7H), 6.82-6.78 (m, 2H), 5.42-5.37(m, 1H), 3.33 (s, 3H), 3.23 (1H), 2.97 (1H, B of ABX, J=13.3, 11.4Hz),2.83-2.75 (m, 4H), 2.49 (q, 2H, J=6.4, 3.3Hz), 1.31 (t, 3H, J=7.5Hz).

(S)-4-{2-[2-(4-Ethyl-2,3-dioxopiperazin-1-yl)acetamido]-2-(4-ethylthiazol-2-yl)ethyl}phenylsulfamicacid: ¹H NMR (CD₃OD) δ 7.14 (s, 4H), 7.08 (s, 1H), 5.56-5.51 (m, 1H),4.34 (d, 2H, J=16.2Hz), 3.88 (d, 2H, J=17.6Hz), 3.59-3.40 (m, 3H),3.26-3.14 (m, 3H), 2.98 (1H, B of ABX, J=10.8, 13.9Hz), 2.82 (q, 2H,J=6.9, 15Hz), 1.32 (t, 3H, J=7.5Hz), 1.21 (t, 3H, J=7.2Hz).

(S)-4-{2-(4-Ethylthiazol-2-yl)-2-[2-(5-methyl-2,4-dioxo-3,4-dihydropyrimidin-1(2H)-yl)acetamido]ethyl}phenylsulfamicacid: ¹H NMR (CD₃OD): δ 7.13 (s, 1H), 7.06-7.02 (m, 4H), 6.95 (s, 1H),5.42-5.31 (m, 1H), 4.43-4.18 (dd, 2H, J=16.5Hz), 3.24-2.93 (m, 2H),2.74-2.69 (q, 2H, J=7.3Hz), 1.79 (s, 3H), 1.22 (t, 3H, J=7.5Hz).

(S)-4-[2-(benzo[d][1,3]dioxole-5-carboxamido)-2-(4-ethylthiazol-2-yl)ethyl]-phenylsulfamicacid: ¹H NMR (CD₃OD) δ 7.25 (d, 1H, J=6.5 Hz), 7.13 (s, 1H), 7.06 (d,2H, J=8.5 Hz), 7.00 (d, 2H, J=8.5 Hz), 6.91 (s, 1H), 6.76 (d, 1H, J=8.1Hz), 5.90 (s, 2H), 5.48 (q, 1H, J=5.0 Hz), 3.32-3.24 (m, 2H), 3.07-2.99(m, 2H), 2.72 (q, 2H, J=7.5 Hz), 1.21 (t, 3H, J=7.5 Hz).

(S)-4-{2-[2-(2,5-Dimethylthiazol-4-yl)acetamido]-2-(4-ethylthiazol-2-yl)ethyl}-phenylsulfamicacid: ¹H NMR (CD₃OD): δ 7.10-7.01 (m, 5H), 5.41 (t, 1H, J=6.9 Hz), 3.58(s, 2H), 3.33-3.01 (m, 2H), 2.82-2.75 (q, 2H, J=7.5 Hz), 2.59 (s, 3H),2.23 (s, 3H), 1.30 (t, 3H, J=7.5 Hz).

(S)-4-{2-[2-(2,4-Dimethylthiazol-5-yl)acetamido]-2-(4-methylthiazol-2-yl)ethyl}-phenylsulfamicacid: ¹H NMR (CD₃OD): δ 8.71-8.68 (d, 1H, J=8.4 Hz), 7.10-7.03 (m, 4H),7.01 (s, 1H), 5.41 (m, 1H), 3.59 (s, 1H), 3.34-2.96 (m, 2H), 2.59 (s,3H), 2.40 (s, 3H), 2.23 (s, 3H).

(S)-4-{2-(4-Ethylthiazol-2-yl)-2-[3-(thiazol-2-yl)propanamido]ethyl}phenylsulfamicacid: ¹H NMR (CD₃OD): δ 7.67-7.65 (m, 1H), 7.49-7.47 (m, 1H), 7.14-7.08(m, 4H), 7.04 (s, 1H), 5.46-5.41 (q, 1H, J=5.1 Hz), 3.58 (s, 2H),3.30-3.25 (m, 3H), 3.02-2.67 (m, 5H), 1.31 (t, 3H, J=7.5 Hz).

(S)-4-{2-(4-Ethylthiazol-2-yl)-2-[2-(4-ethylthiazol-2-yl)acetamido]ethyl}-phenylsulfamicacid: ¹H NMR (CD₃OD): δ 7.04-6.91 (m, 6H), 5.32 (t, 1H, J=5.4 Hz),3.25-2.90 (m, 2H), 2.71-2.61 (m, 4H) 1.93 (s, 2H) 1.22-1.14 (m, 6H).

The second aspect of Category V of the present disclosure relates to2-(thiazol-4-yl) compounds having the formula:

wherein R¹, R⁴, and L are further defined herein in Table X hereinbelow.

TABLE X No. L R¹ R⁴ J360 —C(O)CH₂— phenyl methyl J361 —C(O)CH₂— phenylethyl J362 —C(O)CH₂— phenyl phenyl J363 —C(O)CH₂— phenyl thiophen-2- ylJ364 —C(O)CH₂— phenyl thiazol-2-yl J365 —C(O)CH₂— phenyl oxazol-2-ylJ366 —C(O)CH₂— phenyl isoxazol-3-yl J367 —C(O)CH₂— 3-chlorophenyl methylJ368 —C(O)CH₂— 3-chlorophenyl ethyl J369 —C(O)CH₂— 3-chlorophenyl phenylJ370 —C(O)CH₂— 3-chlorophenyl thiophen-2- yl J371 —C(O)CH₂—3-chlorophenyl thiazol-2-yl J372 —C(O)CH₂— 3-chlorophenyl oxazol-2-ylJ373 —C(O)CH₂— 3-chlorophenyl isoxazol-3-yl J374 —C(O)CH₂—3-methoxyphenyl methyl J375 —C(O)CH₂— 3-methoxyphenyl ethyl J376—C(O)CH₂— 3-methoxyphenyl phenyl J377 —C(O)CH₂— 3-methoxyphenylthiophen-2- yl J378 —C(O)CH₂— 3-methoxyphenyl thiazol-2-yl J379—C(O)CH₂— 3-methoxyphenyl oxazol-2-yl J380 —C(O)CH₂— 3-methoxyphenylisoxazol-3-yl J381 —C(O)CH₂— 3-fluorophenyl methyl J382 —C(O)CH₂—3-fluorophenyl ethyl J383 —C(O)CH₂— 3-fluorophenyl phenyl J384 —C(O)CH₂—3-fluorophenyl thiophen-2- yl J385 —C(O)CH₂— 3-fluorophenyl thiazol-2-ylJ386 —C(O)CH₂— 3-fluorophenyl oxazol-2-yl J387 —C(O)CH₂— 3-fluorophenylisoxazol-3-yl J388 —C(O)CH₂— 2,5-dimethylthiazol-4-yl methyl J389—C(O)CH₂— 2,5-dimethylthiazol-4-yl ethyl J390 —C(O)CH₂—2,5-dimethylthiazol-4-yl phenyl J391 —C(O)CH₂— 2,5-dimethylthiazol-4-ylthiophen-2- yl J392 —C(O)CH₂— 2,5-dimethylthiazol-4-yl thiazol-2-yl J393—C(O)CH₂— 2,5-dimethylthiazol-4-yl oxazol-2-yl J394 —C(O)CH₂—2,5-dimethylthiazol-4-yl isoxazol-3-yl J395 —C(O)CH₂—2,4-dimethylthiazol-5-yl methyl J396 —C(O)CH₂— 2,4-dimethylthiazol-5-ylethyl J397 —C(O)CH₂— 2,4-dimethylthiazol-5-yl phenyl J398 —C(O)CH₂—2,4-dimethylthiazol-5-yl thiophen-2- yl J399 —C(O)CH₂—2,4-dimethylthiazol-5-yl thiazol-2-yl J400 —C(O)CH₂—2,4-dimethylthiazol-5-yl oxazol-2-yl J401 —C(O)CH₂—2,4-dimethylthiazol-5-yl isoxazol-3-yl J402 —C(O)CH₂—4-ethylthiazol-2-yl methyl J403 —C(O)CH₂— 4-ethylthiazol-2-yl ethyl J404—C(O)CH₂— 4-ethylthiazol-2-yl phenyl J405 —C(O)CH₂— 4-ethylthiazol-2-ylthiophen-2- yl J406 —C(O)CH₂— 4-ethylthiazol-2-yl thiazol-2-yl J407—C(O)CH₂— 4-ethylthiazol-2-yl oxazol-2-yl J408 —C(O)CH₂—4-ethylthiazol-2-yl isoxazol-3-yl J409 —C(O)CH₂—3-methyl-1,2,4-oxadiazol-5-yl methyl J410 —C(O)CH₂—3-methyl-1,2,4-oxadiazol-5-yl ethyl J411 —C(O)CH₂—3-methyl-1,2,4-oxadiazol-5-yl phenyl J412 —C(O)CH₂—3-methyl-1,2,4-oxadiazol-5-yl thiophen-2- yl J413 —C(O)CH₂—3-methyl-1,2,4-oxadiazol-5-yl thiazol-2-yl J414 —C(O)CH₂—3-methyl-1,2,4-oxadiazol-5-yl oxazol-2-yl J415 —C(O)CH₂—3-methyl-1,2,4-oxadiazol-5-yl isoxazol-3-yl J416 —C(O)CH₂CH₂— phenylmethyl J417 —C(O)CH₂CH₂— phenyl ethyl J418 —C(O)CH₂CH₂— phenyl phenylJ419 —C(O)CH₂CH₂— phenyl thiophen-2- yl J420 —C(O)CH₂CH₂— phenylthiazol-2-yl J421 —C(O)CH₂CH₂— phenyl oxazol-2-yl J422 —C(O)CH₂CH₂—phenyl isoxazol-3-yl J423 —C(O)CH₂CH₂— 3-chlorophenyl methyl J424—C(O)CH₂CH₂— 3-chlorophenyl ethyl J425 —C(O)CH₂CH₂— 3-chlorophenylphenyl J426 —C(O)CH₂CH₂— 3-chlorophenyl thiophen-2- yl J427 —C(O)CH₂CH₂—3-chlorophenyl thiazol-2-yl J428 —C(O)CH₂CH₂— 3-chlorophenyl oxazol-2-ylJ429 —C(O)CH₂CH₂— 3-chlorophenyl isoxazol-3-yl J430 —C(O)CH₂CH₂—3-methoxyphenyl methyl J431 —C(O)CH₂CH₂— 3-methoxyphenyl ethyl J432—C(O)CH₂CH₂— 3-methoxyphenyl phenyl J433 —C(O)CH₂CH₂— 3-methoxyphenylthiophen-2- yl J434 —C(O)CH₂CH₂— 3-methoxyphenyl thiazol-2-yl J435—C(O)CH₂CH₂— 3-methoxyphenyl oxazol-2-yl J436 —C(O)CH₂CH₂—3-methoxyphenyl isoxazol-3-yl J437 —C(O)CH₂CH₂— 3-fluorophenyl methylJ438 —C(O)CH₂CH₂— 3-fluorophenyl ethyl J439 —C(O)CH₂CH₂— 3-fluorophenylphenyl J440 —C(O)CH₂CH₂— 3-fluorophenyl thiophen-2- yl J441 —C(O)CH₂CH₂—3-fluorophenyl thiazol-2-yl J442 —C(O)CH₂CH₂— 3-fluorophenyl oxazol-2-ylJ443 —C(O)CH₂CH₂— 3-fluorophenyl isoxazol-3-yl J444 —C(O)CH₂CH₂—2,5-dimethylthiazol-4-yl methyl J445 —C(O)CH₂CH₂—2,5-dimethylthiazol-4-yl ethyl J446 —C(O)CH₂CH₂—2,5-dimethylthiazol-4-yl phenyl J447 —C(O)CH₂CH₂—2,5-dimethylthiazol-4-yl thiophen-2- yl J448 —C(O)CH₂CH₂—2,5-dimethylthiazol-4-yl thiazol-2-yl J449 —C(O)CH₂CH₂—2,5-dimethylthiazol-4-yl oxazol-2-yl J450 —C(O)CH₂CH₂—2,5-dimethylthiazol-4-yl isoxazol-3-yl J451 —C(O)CH₂CH₂—2,4-dimethylthiazol-5-yl methyl J452 —C(O)CH₂CH₂—2,4-dimethylthiazol-5-yl ethyl J453 —C(O)CH₂CH₂—2,4-dimethylthiazol-5-yl phenyl J454 —C(O)CH₂CH₂—2,4-dimethylthiazol-5-yl thiophen-2- yl J455 —C(O)CH₂CH₂—2,4-dimethylthiazol-5-yl thiazol-2-yl J456 —C(O)CH₂CH₂—2,4-dimethylthiazol-5-yl oxazol-2-yl J457 —C(O)CH₂CH₂—2,4-dimethylthiazol-5-yl isoxazol-3-yl J458 —C(O)CH₂CH₂—4-ethylthiazol-2-yl methyl J459 —C(O)CH₂CH₂— 4-ethylthiazol-2-yl ethylJ460 —C(O)CH₂CH₂— 4-ethylthiazol-2-yl phenyl J461 —C(O)CH₂CH₂—4-ethylthiazol-2-yl thiophen-2- yl J462 —C(O)CH₂CH₂— 4-ethylthiazol-2-ylthiazol-2-yl J463 —C(O)CH₂CH₂— 4-ethylthiazol-2-yl oxazol-2-yl J464—C(O)CH₂CH₂— 4-ethylthiazol-2-yl isoxazol-3-yl J465 —C(O)CH₂CH₂—3-methyl-1,2,4-oxadiazol-5-yl methyl J466 —C(O)CH₂CH₂—3-methyl-1,2,4-oxadiazol-5-yl ethyl J467 —C(O)CH₂CH₂—3-methyl-1,2,4-oxadiazol-5-yl phenyl J468 —C(O)CH₂CH₂—3-methyl-1,2,4-oxadiazol-5-yl thiophen-2- yl J469 —C(O)CH₂CH₂—3-methyl-1,2,4-oxadiazol-5-yl thiazol-2-yl J470 —C(O)CH₂CH₂—3-methyl-1,2,4-oxadiazol-5-yl oxazol-2-yl J471 —C(O)CH₂CH₂—3-methyl-1,2,4-oxadiazol-5-yl isoxazol-3-yl

The compounds encompassed within the second aspect of Category I of thepresent disclosure can be prepared by the procedure outlined in SchemeII and described in Example 9 herein below.

EXAMPLE 94-((S)-2-(2-(3-chlorophenyl)acetamido)-2-(2-(thiophen-2-yl)thiazol-4-yl)ethyl)phenylsulfamicacid (23)

Preparation of(S)-2-(4-nitrophenyl)-1-[(thiophen-2-yl)thiazol-4-yl]ethanaminehydrobromide salt (22): A mixture of (S)-tert-butyl4-bromo-1-(4-nitrophenyl)-3-oxobutan-2-ylcarbamate, 7, (7.74 g, 20mmol), and thiophen-2-carbothioic acid amide (3.14 g, 22 mmol) in CH₃CN(200 mL) is refluxed for 5 hours. The reaction mixture is cooled to roomtemperature and diethyl ether (50 mL) is added to the solution. Theprecipitate which forms is collected by filtration. The solid is driedunder vacuum to afford 7.14 g (87% yield) of the desired product. ESI+MS 332 (M+1).

Preparation of2-(3-chlorophenyl)-N-{(S)-2-(4-nitrophenyl)-1-[2-(thiophen-2-yl)thiazol-4-yl]ethyl}acetamide(23): To a solution of2-(4-nitrophenyl)-1-(2-thiophene2-ylthiazol-4-yl)ethylamine, 22, (0.41g, 1 mmol) 3-chlorophenylacetic acid (0.170 g, 1 mmol) and1-hydroxybenzotriazole (HOBt) (0.070 g, 0.50 mmol) in DMF (5 mL) at 0°C., is added 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide (EDCI) (0.190g, 1 mmol) followed by triethylamine (0.42 mL, 3 mmol). The mixture isstirred at 0° C. for 30 minutes then at room temperature overnight. Thereaction mixture is diluted with water and extracted with EtOAc. Thecombined organic phase is washed with 1 N aqueous HCl, 5% aqueousNaHCO₃, water and brine, and dried over Na₂SO₄. The solvent is removedin vacuo to afford 0.290 g (60% yield) of the desired product which isused without further purification. ESI− MS 482 (M−1).

Preparation of{4-[2-(3-chlorophenyl)acetylamino]-2-(2-thiophen-2-ylthiazol-4-yl)ethyl]phenyl}sulfamicacid (24):2-(3-chlorophenyl)-N-{(S)-2-(4-nitrophenyl)-1-[2-(thiophene2-yl)thiazol-4-yl]ethyl}acetamide,23, (0.290 g) is dissolved in MeOH (4 mL). A catalytic amount of Pd/C(10% w/w) is added and the mixture is stirred under a hydrogenatmosphere 18 hours. The reaction mixture is filtered through a bed ofCELITE™ and the solvent is removed under reduced pressure. The crudeproduct is dissolved in pyridine (12 mL) and treated with SO₃-pyridine(0.157 g). The reaction is stirred at room temperature for 5 minutesafter which a 7% solution of NH₄OH is added. The mixture is thenconcentrated and the resulting residue is purified by reverse phasechromatography to afford 0.078 g of the desired product as the ammoniumsalt. ¹H NMR (CD3OD) δ 7.61 (d, 1H, J=3.6Hz), 7.58 (d, 1H, J=5.1Hz),7.41-7.35 (m, 1H), 7.28-7.22 (m, 2H), 7.18-6.98 (m, 6H), 5.33 (t, 1H,J=6.6Hz), 3.70 (d, 2H, J=3.9 Hz), 3.23 (1H, A of ABX, J=6.6, 13.8Hz),3.07 (1H, B of ABX, J=8.1, 13.5Hz).

The following are non-limiting examples of compounds encompassed withinthe second aspect of Category V of the present disclosure.

4-((S)-2-(2-(3-Methoxyphenyl)acetamido)-2-(2-(thiophene2-yl)thiazol-4-yl)ethyl)-phenylsulfamicacid: ¹H NMR (CD3OD) δ 8.35 (d, 1H, J=8.7Hz), 7.61-7.57 (m, 2H),7.25-7.20 (m, 2H), 7.25-7.20 (m, 2H), 7.09 (s, 1H), 7.05 (d, 2H,J=4.2Hz), 6.99 (d, 1H, J=8.7Hz), 6.81 (d, 1H, J=7.8Hz), 6.77 (s, 1H),5.30-5.28 (m, 1H), 3.76 (s, 3H), 3.51 (s, 2H), 3.20 (1H, A of ABX,J=6.3, 13.6Hz), 3.06 (1H, B of ABX, J=8.1, 13.8Hz).

4-{(S)-2-(3-Phenylpropanamido)-2-[2-(thiophene2-yl)thiazol-4-yl]ethyl}-phenylsulfamicacid: ¹H NMR (CD3OD) δ 8.30 (d, 1H, J=9Hz), 7.61-7.56 (m, 2H), 7.26-7.14(m, 7H), 7.12 (d, 1H, J=1.5Hz), 7.09 (d, 1H, J=2.1Hz), 6.89 (s, 1H),5.28-5.26 (m, 1H), 3.18 (1H, A of ABX, J=6.2, 13.8Hz), 2.96 (1H, B ofABX, J=8.4, 13.6Hz).

4-{(S)-2-(3-(3-Chlorophenyl)propanamido)-2-[2-(thiophene2-yl)thiazol-4-yl]ethyl}phenylsulfamicacid: ¹H NMR (CD₃OD) δ 7.61-7.56 (m, 3H), 7.22-7.14 (m, 6H), 7.08 (d,1H), 7.00 (d, 1H, J=77.5Hz), 6.870 (s, 1H), 5.25 (t, 1H, J=7. Hz), 3.18(1H, A of ABX, J=6.6, 13.8Hz), 2.97 (1H, B of ABX, J=7.8, 13.8Hz), 2.87(t, 2H, J=7.5Hz), 2.51 (t, 2H, J=7.2 Hz).

4-{(S)-2-[2-(3-Fluorophenyl)acetamido]-2-[2-(thiophen-2-yl)thiazol-4-yl]ethyl}phenylsulfamicacid: ¹H NMR (CD₃OD) δ 7.61-7.57 (m, 2H), 7.32-7.28 (m, 1H), 7.19-7.16(m, 2H), 7.08 (t, 1H, J=4.5Hz), 7.02-6.95 (m, 6H), 5.29 (t, 1H,J=8.1Hz), 3.53 (s, 2H), 3.22 (1H, A of ABX, J=6.6, 13.9Hz), 3.06 (1H, Bof ABX, J=8.4, 13.6Hz).

(S)-4-{2-[2-(3-Methyl-1,2,4-oxadiazol-5-yl)acetamido]-2-(2-phenylthiazol-4-yl)ethyl}phenylsulfamicacid: ¹H NMR (CD₃OD): δ 7.98-7.95 (m, 2H), 7.48-7.46 (m, 3H), 7.23 (s,1H), 7.09-7.05 (m, 4H), 5.33 (t, 1H, J=7.2Hz), 3.33-3.06 (m, 2H), 2.35(s, 3H).

4-{(S)-2-[2-(4-ethyl-2,3-dioxopiperazin-1-yl)acetamido]-2-[2-(thiophen-2-yl)thiazol-4-yl]ethyl}phenylsulfamicacid: ¹H NMR (CD₃OD) δ 7.62 (d, 1H, J=3Hz), 7.58 (d, 1H, J=15.6Hz), 7.27(s, 1H), 7.16 (t, 1H, J=1.5Hz), 5.42-5.32 (m, 1H), 4.31 (d, 1H,J=15.6Hz), 3.91 (d, 1H, J=15.9Hz), 3.60-3.50 (m, 4H), 3.30-3.23 (m, 2H),2.98 (1H, B of ABX, J=9.9, 13.8Hz), 1.21 (t, 3H, J=6.9Hz).

The third aspect of Category V of the present disclosure relates tocompounds having the formula:

wherein the linking unit L comprises a phenyl unit, said linking grouphaving the formula:—C(O)[(CR^(5a)H)][(CR^(6a)H)]—R¹ is hydrogen, R^(6a) is phenyl, R^(5a) is phenyl or substituted phenyland non-limiting examples of the units R², R³, and R^(5a) are furtherexemplified herein below in Table XI.

TABLE XI No. R² R³ R^(5a) K472 methyl hydrogen phenyl K473 methylhydrogen 2-fluorophenyl K474 methyl hydrogen 3-fluorophenyl K475 methylhydrogen 4-fluorophenyl K476 methyl hydrogen 3,4-difluorophenyl K477methyl hydrogen 2-chlorophenyl K478 methyl hydrogen 3-chlorophenyl K479methyl hydrogen 4-chlorophenyl K480 methyl hydrogen 3,4-dichlorophenylK481 methyl hydrogen 2-methoxyphenyl K482 methyl hydrogen3-methoxyphenyl K483 methyl hydrogen 4-methoxyphenyl K484 ethyl hydrogenphenyl K485 ethyl hydrogen 2-fluorophenyl K486 ethyl hydrogen3-fluorophenyl K487 ethyl hydrogen 4-fluorophenyl K488 ethyl hydrogen3,4-difluorophenyl K489 ethyl hydrogen 2-chlorophenyl K490 ethylhydrogen 3-chlorophenyl K491 ethyl hydrogen 4-chlorophenyl K492 ethylhydrogen 3,4-dichlorophenyl K493 ethyl hydrogen 2-methoxyphenyl K494ethyl hydrogen 3-methoxyphenyl K495 ethyl hydrogen 4-methoxyphenyl

The compounds encompassed within the third aspect of Category V of thepresent disclosure can be prepared by the procedure outlined in SchemeIX and described in Example 10 herein below.

EXAMPLE 10(S)-4-(2-(2,3-Diphenylpropanamido)-2-(4-ethylthiazol-2-yl)ethyl)-phenylsulfamicacid (26)

Preparation of(S)—N-[1-(4-ethylthiazol-2-yl)-2-(4-nitrophenyl)ethyl]-2,3-diphenyl-propanamide(25): To a solution of1-(S)-(4-ethylthiazol-2-yl)-2-(4-nitrophenyl)ethyl amine hydrobromide,3, (0.95 g, 2.65 mmol), diphenylpropionic acid (0.60 g, 2.65 mmol) and1-hydroxybenzotriazole (HOBt) (0.180 g, 1.33 mmol) in DMF (10 mL) at 0°,is added 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide (EDCI) (0.502 g,2.62 mmol) followed by triethylamine (1.1 mL, 7.95 mmol). The mixture isstirred at 0° C. for 30 minutes then at room temperature overnight. Thereaction mixture is diluted with water and extracted with EtOAc. Thecombined organic phase is washed with 1 N aqueous HCl, 5% aqueousNaHCO₃, water and brine, and dried over Na₂SO₄. The solvent is removedin vacuo to afford 0.903 g (70% yield) of the desired product which isused without further purification.

Preparation of(S)-4-(2-(2,3-diphenylpropanamido)-2-(4-ethylthiazol-2-yl)ethyl)phenylsulfamicacid (26)(S)—N-[1-(4-ethylthiazol-2-yl)-2-(4-nitrophenyl)ethyl]-2,3-diphenyl-propanamide,25, (0.903 g) is dissolved in MeOH (10 mL). A catalytic amount of Pd/C(10% w/w) is added and the mixture is stirred under a hydrogenatmosphere 18 hours. The reaction mixture is filtered through a bed ofCELITE™ and the solvent is removed under reduced pressure. The crudeproduct is dissolved in pyridine (30 mL) and treated with SO₃-pyridine(0.621 g). The reaction is stirred at room temperature for 5 minutesafter which a 7% solution of NH₄OH is added. The mixture is thenconcentrated and the resulting residue is purified by reverse phasechromatography to afford 0.415 g of the desired product as the ammoniumsalt. ¹H NMR (CD₃OD) δ 8.59-8.52 (m, 1H), 7.37-7.04 (m, 9H), 6.97-6.93(m, 1H), 6.89-6.85 (m, 2H), 5.36-5.32 (m, 1H), 3.91-3.83 (m, 1H), 3.29(1H, A of ABX, obscured by solvent), 3.15 (1H, B of ABX, J=5.4, 33.8Hz),2.99-2.88 (m, 2H), 2.81-2.69 (m, 2H), 1.32-1.25 (m, 3H).

The precursors of many of the Z units which comprise the third aspect ofCategory V are not readily available. The following procedureillustrates an example of the procedure which can be used to providedifferent R^(5a) units according to the present disclosure. Using theprocedure outlined in Scheme X and described in Example 11 the artisancan make modifications without undue experimentation to achieve theR^(5a) units encompassed by the present disclosure.

EXAMPLE 11 2-(2-Methoxyphenyl)-3-phenylpropanoic acid (28)

Preparation of methyl 2-(2-methoxyphenyl)-3-phenylpropanoate (27): A 500mL round-bottom flask is charged with methyl 2-(2-methoxyphenyl)acetate(8.496 g, 47 mmol, 1 eq) and THF (200 mL). The homogeneous mixture iscooled to 0° C. in an ice bath. Lithium diisopropyl amide (23.5 mL of a2.0M solution in heptane/THF) is added, maintaining a temperature lessthan 3° C. The reaction is stirred 45 minutes at this reducedtemperature. Benzyl bromide (5.6 mL, 47 mmol, 1 eq) is added dropwise.The reaction is allowed to gradually warm to room temperature and isstirred for 18 hours. The reaction is quenched with 1N HCl and extracted3 times with equal portions of EtOAc. The combined extracts are washedwith H₂O and brine, dried over Na₂SO₄, filtered, and concentrated. Theresidue is purified over silica to afford 4.433 g (35%) of the desiredcompound. ESI+ MS 293 (M+Na).

Preparation of 2-(2-methoxyphenyl)-3-phenylpropanoic acid (28): Methyl2-(2-methoxyphenyl)-3-phenylpropanoate (4.433 g, 16 mmol, 1 eq) isdissolved in 100 mL of a 1:1 (v:v) mixture of THF and methanol. Sodiumhydroxide (3.28 g, 82 mmol, 5 eq) is added and the reaction mixture isstirred 18 hours at room temperature. The reaction is then poured intoH₂O and the pH is adjusted to 2 via addition of 1N HCl. A whiteprecipitate forms which is removed by filtration. The resulting solutionis extracted with 3 portion of diethyl ether. The extracts are pooled,washed with H₂O and brine, dried over Na₂SO₄, filtered, and concentratedin vacuo. The resulting residue is purified over silica to afford 2.107g (51%) of the desired compound. ESI− MS 255 (M−1), 211 (M-CO₂H).

Intermediate 28 can be carried forward according to the procedureoutlined in Scheme IX and described in Example 10 to produce thefollowing compound according to the third aspect of Category V.

(S)-4-{2-(4-Ethylthiazol-2-yl)-2-[2-(2-methoxyphenyl)-3-phenylpropanamido]-ethyl}phenylsulfamicacid: ¹H NMR (CD₃OD) δ 7.32-7.12 (m, 7H), 7.05-7.02 (m, 1H), 6.99-6.83(m, 4H), 6.80-6.75 (m, 2H), 5.35-5.31 (m, 1H), 4.31-4.26 (m, 1H), 3.75(s, 3H), 3.20-2.90 (m, 4H), 2.79-2.74 (m, 2H), 1.32-1.25 (m, 3H).

The following are further non-limiting examples of compounds accordingto the third aspect of Category I of the present disclosure.

(S)-4-{2-(4-Ethylthiazol-2-yl)-2-[2-(3-fluorophenyl)-3-phenylpropanamido]-ethyl}phenylsulfamicacid: ¹H NMR (CD₃OD) δ 7.33-6.87 (m, 14H), 5.39-5.25 (m, 1H), 3.95-3.83(m, 1H), 3.31-3.10 (m, 1H), 3.05-2.88 (m, 2H), 2.80-2.70 (m, 2H),1.32-1.23 (m, 3H). ¹⁹F NMR δ 47.59.

(S)-4-{2-(4-Ethylthiazol-2-yl)-2-[2-(3-methoxyphenyl)-3-phenylpropanamido]-ethyl}phenylsulfamicacid: ¹H NMR (CD₃OD) δ 7.85 (d, 1H, J=8.4Hz), 7.25-7.20 (m, 1H),7.11-7.02 (m, 4H), 7.01 (s, 1H), 6.90-6.79 (m, 2H), 5.45-5.40 (m, 1H),4.09 (s, 2H), 3.79 (s, 3H), 3.12-3.08 (m, 2H), 1.10 (s, 9H).

The fourth aspect of Category V of the present disclosure relates tocompounds having the formula:

wherein the linking unit L comprises a phenyl unit, said linking grouphaving the formula:—C(O)[(CR^(5a)H)][(CR^(6a)H]—R¹ is hydrogen, R^(6a) is phenyl, R^(5a) is substituted or unsubstitutedheteroaryl and the units R², R³, and R^(5a) are further exemplifiedherein below in Table XII.

TABLE XII No. R² R³ R^(5a) L496 methyl hydrogen3-methyl-1,2,4-oxadiazol-5-yl L497 methyl hydrogen thiophen-2-yl L498methyl hydrogen thiazol-2-yl L499 methyl hydrogen oxazol-2-yl L500methyl hydrogen isoxazol-3-yl L501 ethyl hydrogen3-methyl-1,2,4-oxadiazol-5-yl L502 ethyl hydrogen thiophen-2-yl L503ethyl hydrogen thiazol-2-yl L504 ethyl hydrogen oxazol-2-yl L505 ethylhydrogen isoxazol-3-yl L506 ethyl methyl 3-methyl-1,2,4-oxadiazol-5-ylL507 ethyl methyl thiophen-2-yl L508 ethyl methyl thiazol-2-yl L509ethyl methyl oxazol-2-yl L510 ethyl methyl isoxazol-3-yl L511thiophen-2-yl hydrogen 3-methyl-1,2,4-oxadiazol-5-yl L512 thiophen-2-ylhydrogen thiophen-2-yl L513 thiophen-2-yl hydrogen thiazol-2-yl L514thiophen-2-yl hydrogen oxazol-2-yl L515 thiophen-2-yl hydrogenisoxazol-3-yl L516 isoxazol-3-yl hydrogen 3-methyl-1,2,4-oxadiazol-5-ylL517 isoxazol-3-yl hydrogen thiophen-2-yl L518 isoxazol-3-yl hydrogenthiazol-2-yl L519 isoxazol-3-yl hydrogen oxazol-2-yl L520 isoxazol-3-ylhydrogen isoxazol-3-yl

The compounds encompassed within the fourth aspect of Category V of thepresent disclosure can be prepared by the procedure outlined in Scheme Vand described in Example 5 herein below.

EXAMPLE 124-{(S)-2-(4-Ethylthiazol-2-yl)-2-[2-(3-methyl-1,2,4-oxadiazol-5-yl)-3-phenylpropanamido]ethyl}phenylsulfamicacid (31)

Preparation ofethyl-2-benzyl-3-[(S)-1-(4-ethylthiazol-2-yl)-2-(4-nitrophenyl)-ethylamino]-3-oxopropanoate(29): To a solution of1-(S)-(4-ethylthiazol-2-yl)-2-(4-nitrophenyl)ethyl amine hydrobromide,3, (0.406 g, 1.13 mmol), 2-benzyl-3-ethoxy-3-oxopropanoic acid (0.277 g)and 1-hydroxybenzotriazole (HOBt) (0.191 g, 1.41 mmol) in DMF (10 mL) at0°, is added 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide (EDCI) (0.240g, 1.25 mmol) followed by diisopropylethylamine (DIPEA) (0.306 g). Themixture is stirred at 0° C. for 30 minutes then at room temperatureovernight. The reaction mixture is diluted with water and extracted withEtOAc. The combined organic phase is washed with 1 N aqueous HCl, 5%aqueous NaHCO₃, water and brine, and dried over Na₂SO₄. The solvent isremoved in vacuo to afford 0.169 g (31% yield) of the desired productwhich is used without further purification.

Preparation ofN—[(S)-1-(4-ethylthiazol-2-yl)-2-(4-nitrophenyl)ethyl]-2-(3-methyl-1,2,4-oxadiazol-5-yl)-3-phenylpropanamide(30): Ethyl2-benzyl-3-((S)-1-(4-ethylthiazol-2-yl)-2-(4-nitrophenyl)ethylamino)-3-oxopropanoateis dissolved in toluene (5 mL) and heated to reflux. Potassium carbonate(80 mg) and acetamide oxime (43 mg) are added. and treated with 80 mgpotassium carbonate and 43 mg acetamide oxime at reflux. The reactionmixture is cooled to room temperature, filtered and concentrated. Theresidue is chromatographed over silica to afford 0.221 g (94%) of thedesired product as a yellow oil.

Preparation of4-{(S)-2-(4-ethylthiazol-2-yl)-2-[2-(3-methyl-1,2,4-oxadiazol-5-yl)-3-phenylpropanamido]ethyl}phenylsulfamicacid (31):N—[(S)-1-(4-ethylthiazol-2-yl)-2-(4-nitrophenyl)ethyl]-2-(3-methyl-1,2,4-oxadiazol-5-yl)-3-phenylpropanamide,30, (0.221 g) and tin (II) chloride (507 mg, 2.2 mmol) are dissolved inEtOH (25 mL) and the solution is brought to reflux 4 hours. The solventis removed in vacuo and the resulting residue is dissolved in EtOAc. Asaturated solution of NaHCO₃ (50 mL) is added and the solution isstirred 1 hour. The organic layer is separated and the aqueous layerextracted twice with EtOAc. The combined organic layers are dried(Na₂SO₄), filtered and concentrated to a residue which is dissolved inpyridine (0.143 g) and treated with SO₃-pyridine (0.143 g). The reactionis stirred at room temperature for 5 minutes after which a 7% solutionof NH₄OH is added. The mixture is then concentrated and the resultingresidue is purified by reverse phase chromatography to afford 0.071 g ofthe desired product as the ammonium salt. ¹H NMR (CD₃OD): δ 7.29-6.87(m, 10H), 5.38-5.30 (m, 1H), 4.37-4.30 (m, 1H), 3.42-2.74 (m, 6H),2.38-2.33 (m, 3H), 1.34-1.28 (m, 3H).

Category VI of the present disclosure relates to 2-(thiazol-2-yl)compounds having the formula:

wherein R¹, R², R³, and L are further defined herein in Table XIIIherein below.

TABLE XIII No. R² R³ R¹ M521 ethyl hydrogen thiophen-2-yl M522 ethylhydrogen thiazol-2-yl M523 ethyl hydrogen oxazol-2-yl M524 ethylhydrogen isoxazol-3-yl M525 ethyl hydrogen imidazol-2-yl M526 ethylhydrogen isoxazol-3-yl M527 ethyl hydrogen oxazol-4-yl M528 ethylhydrogen isoxazol-4-yl M529 ethyl hydrogen thiophen-4-yl M530 ethylhydrogen thiazol-4-yl M531 ethyl methyl methyl M532 ethyl methyl ethylM533 ethyl methyl propyl M534 ethyl methyl iso-propyl M535 ethyl methylbutyl M536 ethyl methyl phenyl M537 ethyl methyl benzyl M538 ethylmethyl 2-fluorophenyl M539 ethyl methyl 3-fluorophenyl M540 ethyl methyl4-fluorophenyl M541 phenyl hydrogen methyl M542 phenyl hydrogen ethylM543 phenyl hydrogen propyl M544 phenyl hydrogen iso-propyl M545 phenylhydrogen butyl M546 phenyl hydrogen phenyl M547 phenyl hydrogen benzylM548 phenyl hydrogen 2-fluorophenyl M549 phenyl hydrogen 3-fluorophenylM550 phenyl hydrogen 4-fluorophenyl M551 thiophen-2-yl hydrogen methylM552 thiophen-2-yl hydrogen ethyl M553 thiophen-2-yl hydrogen propylM554 thiophen-2-yl hydrogen iso-propyl M555 thiophen-2-yl hydrogen butylM556 thiophen-2-yl hydrogen phenyl M557 thiophen-2-yl hydrogen benzylM558 thiophen-2-yl hydrogen 2-fluorophenyl M559 thiophen-2-yl hydrogen3-fluorophenyl M560 thiophen-2-yl hydrogen 4-fluorophenyl

The compounds encompassed within Category VI of the present disclosurecan be prepared by the procedure outlined in Scheme XII and described inExample 13 herein below.

EXAMPLE 13(S)-4-[2-(4-Ethylthiazol-2-yl)-2-(4-oxo-4-phenylbutanamido)ethyl]-phenylsulfamicacid (33)

Preparation of(S)—N-[1-(4-ethylthiazol-2-yl)-2-(4-nitrophenyl)ethyl]-4-oxo-4-phenylbutanamide(32): 3-Benzoylpropionic acid (0.250 g) is dissolved in CH₂Cl₂ (5 mL),N-methyl imidazole (0.333 mL) is added and the resulting solution iscooled to 0° C. after which a solution of thionyl chloride (0.320 g) inCH₂Cl₂ (2 mL) is added dropwise. After 0.5 hours(S)-1-(4-ethylthiazol-2-yl)-2-(4-nitrophenyl)ethanamine, 3, (0.388 g) isadded. The reaction is stirred for 18 hours at room temperature and thenconcentrated in vacuo. The resulting residue is dissolved in EtOAc andwashed with 1N HCl and brine. The solution is dried over Na₂SO₄,filtered, and concentrated and the crude material purified over silicato afford 0.415 g of the desired product.

Preparation of(S)-4-[2-(4-ethylthiazol-2-yl)-2-(4-oxo-4-phenylbutanamido)-ethyl]phenylsulfamicacid (33):(S)—N-[1-(4-ethylthiazol-2-yl)-2-(4-nitrophenyl)ethyl]-2,3-diphenyl-propanamide,32, (0.2 g) is dissolved in MeOH (15 mL). A catalytic amount of Pd/C(10% w/w) is added and the mixture is stirred under a hydrogenatmosphere 18 hours. The reaction mixture is filtered through a bed ofCELITE™ and the solvent is removed under reduced pressure. The crudeproduct is dissolved in pyridine (5 mL) and treated with SO₃-pyridine(0.153 g). The reaction is stirred at room temperature for 5 minutesafter which a 7% solution of NH₄OH is added. The mixture is thenconcentrated and the resulting residue is purified by reverse phasechromatography to afford 0.090 g of the desired product as the ammoniumsalt. ¹H NMR (CD₃OD) δ 8.68 (d, 1H, J=8.2 Hz), 8.00 (d, 2H, J=7.2 Hz),7.80-7.50 (m, 3H), 7.12 (s, 4H), 7.03 (s, 1H), 5.46-5.38 (m, 1H),3.29-3.14 (m, 2H), 3.06-2.99 (m, 2H), 2.83 (q, 2H, J=7.5 Hz), 2.69-2.54(m, 2H), 1.33 (t, 3H, J=7.5 Hz).

The following are non-limiting examples of compounds encompassed withinCategory II of the present disclosure. The intermediate nitro compoundsof the following can be prepared by coupling the appropriate4-oxo-carboxcylic acid with intermediate 3 under the conditionsdescribed herein above for the formation of intermediate 4 of scheme I.

(S)-4-(2-(4-Ethylthiazol-2-yl)-2-(5-methyl-4-oxohexanamido)ethyl)phenylsulfamicacid: ¹H NMR (CD₃OD) δ 8.59 (d, 1H, J=8.1 Hz), 7.14 (s, 4H), 7.08 (t,1H, J=13.0 Hz), 5.40-5.35 (m, 1H), 3.37-3.27 (m, 2H), 3.04-2.97 (m, 1H),2.83-2.61 (m, 4H), 2.54-2.36 (m, 3H), 1.33 (t, 2H, J=7.3 Hz), 1.09 (dd,6H, J=7.0, 2.2 Hz).

(S)-4-{2-[4-(3,4-Dihydro-2H-benzo[b][1,4]dioxepin-7-yl)-4-oxobutanamido]-2-(4-ethylthiazol-2-yl)ethyl}phenylsulfamicacid: ¹H NMR(CD₃OD) δ 8.64 (d, 1H, J=8.4 Hz), 7.60 (d, 2H, J=10.6 Hz),7.11 (s, 3H), 7.04 (d, 2H, J=5.5 Hz), 5.42-5.40 (m, 1H), 4.30-4.22 (m,4H), 3.20-2.98 (m, 4H), 2.82 (q, 2H, J=7.3 Hz), 2.67-2.48 (m, 2H), 2.23(t, 2H, J=5.5 Hz), 1.32 (t, 3H, J=7.3 Hz).

(S)-4-{2-[4-(2,3-Dimethoxyphenyl)-4-oxobutanamido]-2-(4-ethylthiazol-2-yl)ethyl}phenylsulfamicacid: ¹H NMR (CD₃OD), δ 8.64 (d, 1H, J=8.1 Hz), 7.21-7.11 (m, 7H), 7.02(s, 1H), 5.42 (q, 1H, J=5.9 Hz), 3.90 (d, 3H, J=3.3 Hz), 3.88 (d, 3H,J=2.9 Hz), 3.22-3.18 (m, 2H), 3.07-2.99 (m, 2H), 2.83 (q, 2H, J=7.3 Hz),2.63-2.54 (m, 2H), 1.34 (t, 3H, J=7.69 Hz).

(S)-4-{2-(4-Ethylthiazol-2-yl)-2-[4-oxo-4-(pyridin-2-yl)butanamido]ethyl}-phenylsulfamicacid: ¹H NMR (CD₃OD) δ 8.60 (d, 1H, J=12.8 Hz), 7.91-7.81 (m, 2H),7.48-7.44 (m, 1H), 7.22-7.21 (m, 1H), 6.99 (s, 3H), 6.91 (s, 1H), 5.30(q, 1H, J=5.4 Hz), 3.36 (q, 2H, J=7.0 Hz), 3.21-3.15 (m, 1H), 2.91-2.85(m, 1H), 2.74 (q, 2H, J=10.4 Hz), 2.57-2.50 (m, 2H), 1.20 (t, 3H, J=7.5Hz).

(S)-4-{2-[4-(2,3-dihydrobenzo[b][1,4]dioxin-6-yl)-4-oxobutanamido]-2-(4-ethylthiazol-2-yl)ethyl}phenylsulfamicacid: ¹H NMR (CD₃OD) δ 7.52-7.47 (m, 2H), 7.11 (s, 4H), 7.03 (s, 1H),6.95 (d, 1H, J=8.4 Hz), 5.41 (q, 1H, J=3.7 Hz), 4.31 (d, 4H, J=5.5 Hz),3.24-3.12 (m, 2H), 3.06-2.98 (m, 2H), 2.83 (q, 2H, J=7.3 Hz), 2.62-2.53(m, 2H), 1.33 (t, 3H, J=7.3 Hz).

(S)-4-[2-(4-tert-butoxy-4-oxobutanamido)-2-(4-ethylthiazol-2-yl)ethyl]phenylsulfamicacid: ¹H NMR (CD₃OD), δ 7.10 (s 4H), 7.02 (s, 1H), 5.41 (q, 1H, J=3.7Hz), 3.30-3.25 (m, 1H), 3.06-2.99 (m, 1H), 2.83 (q, 2H, J=7.3 Hz),2.52-2.40 (m, 4H), 1.42 (s, 9H), 1.33 (t, 3H, J=7.3 Hz).

(S)-4-[2-(4-ethoxy-4-oxobutanamido)-2-(4-ethylthiazol-2-yl)ethyl]phenylsulfamicacid: ¹H NMR (CD₃OD) δ 8.62 (d, 1H, J=8.4 Hz), 7.10 (s, 4H), 7.02 (s,1H), 5.40 (q, 1H, 3.7 Hz), 4.15 (q, 2H, J=7.3 Hz), 3.28-3.25 (m, 1H),3.05-3.02 (m, 1H), 2.82 (q, 2H, J=4.4 Hz), 2.54-2.48 (m, 2H), 1.33 (t,3H, J=7.3 Hz), 1.24 (t, 3H, J=7.0 Hz).

The first aspect of Category VII of the present disclosure relates to2-(thiazol-2-yl) compounds having the formula:

wherein non-limiting examples of R¹, R², and R³ are further describedherein below in Table XIV.

TABLE XIV No. R² R³ R¹ N561 methyl hydrogen phenyl N562 methyl hydrogenbenzyl N563 methyl hydrogen 2-fluorophenyl N564 methyl hydrogen3-fluorophenyl N565 methyl hydrogen 4-fluorophenyl N566 methyl hydrogen2-chlorophenyl N567 methyl hydrogen 3-chlorophenyl N568 methyl hydrogen4-chlorophenyl N569 ethyl hydrogen phenyl N570 ethyl hydrogen benzylN571 ethyl hydrogen 2-fluorophenyl N572 ethyl hydrogen 3-fluorophenylN573 ethyl hydrogen 4-fluorophenyl N574 ethyl hydrogen 2-chlorophenylN575 ethyl hydrogen 3-chlorophenyl N576 ethyl hydrogen 4-chlorophenylN577 thiene-2-yl hydrogen phenyl N578 thiene-2-yl hydrogen benzyl N579thiene-2-yl hydrogen 2-fluorophenyl N580 thiene-2-yl hydrogen3-fluorophenyl N581 thiene-2-yl hydrogen 4-fluorophenyl N582 thiene-2-ylhydrogen 2-chlorophenyl N583 thiene-2-yl hydrogen 3-chlorophenyl N584thiene-2-yl hydrogen 4-chlorophenyl

The compounds encompassed within Category VII of the present disclosurecan be prepared by the procedure outlined in Scheme XIII and describedin Example 14 herein below.

EXAMPLE 14(S)-4-(2-(3-Benzylureido)-2-(4-ethylthiazol-2-yl)ethyl)phenylsulfamicacid (35)

Preparation of(S)-1-benzyl-3-[1-(4-ethylthiazol-2-yl)-2-(4-nitrophenyl)ethyl]urea(34): To a solution of1-(S)-(4-ethylthiazol-2-yl)-2-(4-nitrophenyl)ethyl amine hydrobromide,3, (0.360 g, 1 mmol) and Et₃N (0.42 mL, 3 mmol) in 10 mL CH₂Cl₂ is addedbenzyl isocyanate (0.12 mL, 1 mmol). The mixture is stirred at roomtemperature for 18 hours. The product is isolated by filtration toafford 0.425 g (96% yield) of the desired product which is used withoutfurther purification.

Preparation of(S)-4-(2-(3-benzylureido)-2-(4-ethylthiazol-2-yl)ethyl)phenylsulfamicacid (35):(S)-1-benzyl-3-[1-(4-ethylthiazol-2-yl)-2-(4-nitrophenyl)ethyl]urea, 34,(0.425 g) is dissolved in MeOH (4 mL). A catalytic amount of Pd/C (10%w/w) is added and the mixture is stirred under a hydrogen atmosphere 18hours. The reaction mixture is filtered through a bed of CELITE™ and thesolvent is removed under reduced pressure. The crude product isdissolved in pyridine (12 mL) and treated with SO₃-pyridine (0.220 g).The reaction is stirred at room temperature for 5 minutes after which a7% solution of NH₄OH is added. The mixture is then concentrated and theresulting residue is purified by reverse phase chromatography to afford0.143 g of the desired product as the ammonium salt. ¹H NMR (CD₃OD) δ7.32-7.30 (m, 2H), 7.29-7.22 (m, 3H), 7.12-7.00 (m, 4H), 6.84 (d, 1H,J=8.1Hz), 5.35-5.30 (m, 1H), 4.29 (s, 2H), 3.27-3.22 (m, 3H), 3.11-3.04(m, 3H), 2.81 (q, 2H, J=10.2, 13.0Hz), 1.31 (t, 3H, J=4.5Hz).

The following is a non-limiting examples of compounds encompassed withinthe first aspect of Category VII of the present disclosure.

4-{[(S)-2-(2-Ethylthiazol-4-yl)-2-(3-(R)-methoxy-1-oxo-3-phenylpropan-2-yl)ureido]ethyl}phenylsulfamicacid: ¹H NMR (CD₃OD) δ 7.36-7.26 (m, 3H), 7.19-7.17 (m, 2H), 7.10-7.06(m, 2H), 6.90-6.86 (m, 3H), 5.12-5.06 (m, 1H), 4.60-4.55 (m, 1H), 3.69(s, 3H) 3.12-2.98 (m, 6H), 1.44-1.38 (m, 3H).

The second aspect of Category VII of the present disclosure relates to2-(thiazol-4-yl) compounds having the formula:

wherein non-limiting examples of R¹ and R⁴ are further described hereinbelow in Table XV.

TABLE XV No. R¹ R⁴ O585 methyl methyl O586 ethyl methyl O587 n-propylmethyl O588 iso-propyl methyl O589 phenyl methyl O590 benzyl methyl O5912-fluorophenyl methyl O592 2-chlorophenyl methyl O593 thiophen-2-ylmethyl O594 thiazol-2-yl methyl O595 oxazol-2-yl methyl O596isoxazol-3-yl methyl O597 methyl ethyl O598 ethyl ethyl O599 n-propylethyl O600 iso-propyl ethyl O601 phenyl ethyl O602 benzyl ethyl O6032-fluorophenyl ethyl O604 2-chlorophenyl ethyl O605 thiophen-2-yl ethylO606 thiazol-2-yl ethyl O607 oxazol-2-yl ethyl O608 isoxazol-3-yl ethylO609 methyl thiophen-2-yl O610 ethyl thiophen-2-yl O611 n-propylthiophen-2-yl O612 iso-propyl thiophen-2-yl O613 phenyl thiophen-2-ylO614 benzyl thiophen-2-yl O615 2-fluorophenyl thiophen-2-yl O6162-chlorophenyl thiophen-2-yl O617 thiophen-2-yl thiophen-2-yl O618thiazol-2-yl thiophen-2-yl O619 oxazol-2-yl thiophen-2-yl O620isoxazol-3-yl thiophen-2-yl O621 methyl thiazol-2-yl O622 ethylthiazol-2-yl O623 n-propyl thiazol-2-yl O624 iso-propyl thiazol-2-ylO625 phenyl thiazol-2-yl O626 benzyl thiazol-2-yl O627 2-fluorophenylthiazol-2-yl O628 2-chlorophenyl thiazol-2-yl O629 thiophen-2-ylthiazol-2-yl O630 thiazol-2-yl thiazol-2-yl O631 oxazol-2-ylthiazol-2-yl O632 isoxazol-3-yl thiazol-2-yl O633 methyl oxazol-2-ylO634 ethyl oxazol-2-yl O635 n-propyl oxazol-2-yl O636 iso-propyloxazol-2-yl O637 phenyl oxazol-2-yl O638 benzyl oxazol-2-yl O6392-fluorophenyl oxazol-2-yl O640 2-chlorophenyl oxazol-2-yl O641thiophen-2-yl oxazol-2-yl O642 thiazol-2-yl oxazol-2-yl O643 oxazol-2-yloxazol-2-yl O644 isoxazol-3-yl oxazol-2-yl

The compounds encompassed within the second aspect of Category VII ofthe present disclosure can be prepared by the procedure outlined inScheme XIV and described in Example 14 herein below.

EXAMPLE 154-{(S)-2-(3-Benzylureido)-2-[2-(thiophen-2-yl)thiazol-4-yl]ethyl}-phenylsulfamicacid (37)

Preparation of1-benzyl-3-{(S)-2-(4-nitrophenyl)-1-[2-(thiophen-2-yl)thiazol-4-yl]ethyl}urea(36): To a solution of(S)-2-(4-nitrophenyl)-1-[(2-thiophen-2-yl)thiazol-4-yl)ethan-aminehydrobromide salt, 8, and Et₃N (0.42 mL, 3 mmol) in 10 mL DCM is addedbenzyl isocyanate (0.12 mL, 1 mmol). The mixture is stirred at roomtemperature for 18 hours. The product is isolated by filtration toafford 0.445 g (96% yield) of the desired product which is used withoutfurther purification.

Preparation of4-{(S)-2-(3-benzylureido)-2-[2-(thiophen-2-yl)thiazol-4-yl]ethyl}phenylsulfamicacid (37):1-Benzyl-3-{(S)-2-(4-nitrophenyl)-1-[2-(thiophen-2-yl)thiazol-4-yl]ethyl}urea,36, (0.445 g) is dissolved in MeOH (10 mL) and CH₂Cl₂ (5 mL). Acatalytic amount of Pd/C (10% w/w) is added and the mixture is stirredunder a hydrogen atmosphere 18 hours. The reaction mixture is filteredthrough a bed of CELITE™ and the solvent is removed under reducedpressure. The crude product is dissolved in pyridine (12 mL) and treatedwith SO₃-pyridine (0.110 g). The reaction is stirred at room temperaturefor 5 minutes after which a 7% solution of NH₄OH is added. The mixtureis then concentrated and the resulting residue is purified by reversephase chromatography to afford 0.080 g of the desired product as theammonium salt. ¹H NMR (CD₃OD) δ 7.61 (d, 1H, J=2.1Hz), 7.58 (d, 1H,J=6Hz), 7.33-7.22 (m, 4H), 7.17-7.14 (m, 1H), 7.09-6.94 (m, 6H), 5.16(t, 1H, J=6.6Hz), 4.13 (s, 2H), 3.14-3.11 (m, 2H).

Category VIII of the present disclosure relates to 2-(thiazol-4-yl)compounds having the formula:

wherein R¹, R⁴, and L are further defined herein in Table XVI hereinbelow.

TABLE XVI No. R⁴ L R¹ P645 methyl —SO₂— methyl P646 ethyl —SO₂— methylP647 phenyl —SO₂— methyl P648 thiophen-2-yl —SO₂— methyl P649 methyl—SO₂— trifluoromethyl P650 ethyl —SO₂— trifluoromethyl P651 phenyl —SO₂—trifluoromethyl P652 thiophen-2-yl —SO₂— trifluoromethyl P653 methyl—SO₂— ethyl P654 ethyl —SO₂— ethyl P655 phenyl —SO₂— ethyl P656thiophen-2-yl —SO₂— ethyl P657 methyl —SO₂— 2,2,2-trifluoroethyl P658ethyl —SO₂— 2,2,2-trifluoroethyl P659 phenyl —SO₂— 2,2,2-trifluoroethylP660 thiophen-2-yl —SO₂— 2,2,2-trifluoroethyl P661 methyl —SO₂— phenylP662 ethyl —SO₂— phenyl P663 phenyl —SO₂— phenyl P664 thiophen-2-yl—SO₂— phenyl P665 methyl —SO₂— 4-fluorophenyl P666 ethyl —SO₂—4-fluorophenyl P667 phenyl —SO₂— 4-fluorophenyl P668 thiophen-2-yl —SO₂—4-fluorophenyl P669 methyl —SO₂— 3,4-dihydro-2H-benzo[b][1,4]oxazin-7-ylP670 ethyl —SO₂— 3,4-dihydro-2H-benzo[b][1,4]oxazin-7-yl P671 phenyl—SO₂— 3,4-dihydro-2H-benzo[b][1,4]oxazin-7-yl P672 thiophen-2-yl —SO₂—3,4-dihydro-2H-benzo[b][1,4]oxazin-7-yl P673 methyl —SO₂—1-methyl-1H-imidazol-4-yl P674 ethyl —SO₂— 1-methyl-1H-imidazol-4-ylP675 phenyl —SO₂— 1-methyl-1H-imidazol-4-yl P676 thiophen-2-yl —SO₂—1-methyl-1H-imidazol-4-yl P678 methyl —SO₂— 4-acetamidophenyl P679 ethyl—SO₂— 4-acetamidophenyl P680 phenyl —SO₂— 4-acetamidophenyl P681thiophen-2-yl —SO₂— 4-acetamidophenyl P682 methyl —SO₂CH₂— phenyl P683ethyl —SO₂CH₂— phenyl P684 phenyl —SO₂CH₂— phenyl P685 thiophen-2-yl—SO₂CH₂— phenyl P686 methyl —SO₂CH₂— (4-methylcarboxyphenyl)methyl P687ethyl —SO₂CH₂— (4-methylcarboxyphenyl)methyl P688 phenyl —SO₂CH₂—(4-methylcarboxyphenyl)methyl P689 thiophen-2-yl —SO₂CH₂—(4-methylcarboxyphenyl)methyl P690 methyl —SO₂CH₂—(2-methylthiazol-4-yl)methyl P691 ethyl —SO₂CH₂—(2-methylthiazol-4-yl)methyl P692 phenyl —SO₂CH₂—(2-methylthiazol-4-yl)methyl P693 thiophen-2-yl —SO₂CH₂—(2-methylthiazol-4-yl)methyl P694 methyl —SO₂CH₂CH₂— phenyl P695 ethyl—SO₂CH₂CH₂— phenyl P696 phenyl —SO₂CH₂CH₂— phenyl P697 thiophen-2-yl—SO₂CH₂CH₂— phenyl

The compounds encompassed within Category VIII of the present disclosurecan be prepared by the procedure outlined in Scheme XV and described inExample 16 herein below.

EXAMPLE 16{4-(S)-[2-Phenylmethanesulfonylamino-2-(2-thiophen-2-ylthiazol-4-yl)ethyl]phenyl}sulfamicacid (39)

Preparation of(S)—N-{2-(4-nitrophenyl)-1-[2-(thiophen-2-yl)thiazol-4-yl]ethyl}-1-phenylmethanesulfonamide(38): To a suspension of2-(4-nitrophenyl)-1-(2-thiophene2-ylthiazol-4-yl)ethylamine, 8, (330 mg,0.80 mmol) in CH₂Cl₂ (6 mL) at 0° C. is added diisopropylethylamine(0.30 mL, 1.6 mmol) followed by phenylmethanesulfonyl chloride (167 mg,0.88 mmol). The reaction mixture is stirred at room temperature for 14hours. The mixture is diluted with CH₂Cl₂ and washed with sat. NaHCO₃followed by brine, dried (Na₂SO₄), filtered and concentrated in vacuo.The resulting residue is purified over silica to afford 210 mg of thedesired product as a white solid.

Preparation of{4-(S)-[2-phenylmethanesulfonylamino-2-(2-thiophen-2-ylthiazol-4-yl)ethyl]phenyl}sulfamicacid (39):(S)—N-{2-(4-nitrophenyl)-1-[2-(thiophen-2-yl)thiazol-4-yl]ethyl}-1-phenylmethanesulfonamide,38, (210 mg, 0.41 mmol) is dissolved in MeOH (4 mL). A catalytic amountof Pd/C (10% w/w) is added and the mixture is stirred under a hydrogenatmosphere 18 hours. The reaction mixture is filtered through a bed ofCELITE™ and the solvent is removed under reduced pressure. The crudeproduct is dissolved in pyridine (12 mL) and treated with SO₃-pyridine(197 mg, 1.23 mmol). The reaction is stirred at room temperature for 5minutes after which a 7% solution of NH₄OH is added. The mixture is thenconcentrated and the resulting residue is purified by reverse phasechromatography to afford 0.060 g of the desired product as the ammoniumsalt. ¹H NMR (300 MHz, MeOH-d₄) δ 7.52-7.63 (m, 6.70-7.28 (m, 11H), 4.75(t, J=7.2 Hz, 1H), 3.95-4.09 (m, 2H), 3.20 (dd, J=13.5 and 7.8 Hz, 1H),3.05 (dd, J=13.5 and 7.8 Hz, 1H). 1013770

Intermediates for use in Step (a) of Scheme XV can be convenientlyprepared by the procedure outlined herein below in Scheme XVI anddescribed in Example 17.

EXAMPLE 17 (2-Methylthiazol-4-yl)methanesulfonyl chloride (41)

Preparation of sodium (2-methylthiazol-4-yl)methanesulfonate (40):4-Chloromethyl-2-methylthiazole (250 mg, 1.69 mmol) is dissolved in H₂O(2 mL) and treated with sodium sulfite (224 mg, 1.78 mmol). The reactionmixture is subjected to microwave irradiation for 20 minutes at 200° C.The reaction mixture is diluted with H₂O (30 mL) and washed with EtOAc(2×25 mL). The aqueous layer is concentrated to afford 0.368 g of thedesired product as a yellow solid. LC/MS ESI+ 194 (M+1, free acid).

Preparation of (2-methylthiazol-4-yl)methanesulfonyl chloride (41):Sodium (2-methylthiazol-4-yl)methanesulfonate, 40, (357 mg, 1.66 mmol)is dissolved in phosphorous oxychloride (6 mL) and is treated withphosphorous pentachloride (345 mg, 1.66 mmol). The reaction mixture isstirred at 50° C. for 3 hours, then allowed to cool to room temperature.The solvent is removed under reduced pressure and the residue isre-dissolved in CH₂Cl₂ (40 mL) and is washed with sat. NaHCO₃ and brine.The organic layer is dried over MgSO₄, filtered, and the solvent removedin vacuo to afford 0.095 g of the desired product as a brown oil. LC/MSESI+ 211 (M+1). Intermediates are obtained in sufficient purity to becarried forward according to Scheme IX without the need for furtherpurification.

4-{(S)-2-[(2-methylthiazol-4-yl)methylsulfonamido]-2-[2-(thiophen-2-yl)thiazol-4-yl]ethyl}phenylsulfamicacid: ¹H NMR (CD₃OD): δ 7.71-7.66 (m, 2H), 7.27-7.10 (m, 7H), 4.87 (t,1H, J=7.3 Hz), 4.30-4.16 (q, 2H, J=13.2 Hz), 3.34-3.13 (m, 2H), 2.70 (s,3H).

The following are non-limiting examples of compounds encompassed withinCategory VIII of the present disclosure.

{4-(S)-[2-Phenylmethanesulfonylamino-2-(2-ethylthiazol-4-yl)ethyl]phenyl}-sulfamicacid: ¹H NMR (300 MHz, MeOH-d₄) δ 7.27-7.32 (m, 3H), 7.16-7.20 (m, 3H),7.05-7.6 (m, 2H), 6.96 (d, J=8.4 Hz, 2H), 4.70 (t, J=9.0 Hz, 1H),3.91-4.02 (m, 2H), 2.95-3.18 (m, 4H), 1.41 (t, J=7.5 Hz, 3H).

{4-(S)-[2-(3-Methoxyphenyl)methanesulfonylamino-2-(2-ethylthiazol-4-yl)ethyl]phenyl}sulfamicacid: ¹H NMR (300 MHz, MeOH-d₄) δ 7.20 (t, J=8.1 Hz. 1H), 6.94-7.08 (m,4H), 6.88-6.94 (m, 3H), 6.75-6.80 (m, 1H), 4.67 (t, J=7.2 Hz, 1H),3.90-4.0 (m, 2H), 3.76 (s, 3H), 2.95-3.16 (m, 4H), 1.40 (t, J=7.5 HZ,3H).

(S)-4-{[1-(2-Ethylthiazol-4-yl)-2-(4-sulfoaminophenyl)ethylsulfamoyl]methyl}-benzoicacid methyl ester: ¹H NMR (300 MHz, MeOH-d₄) δ 7.90-7.94-(m, 2H),7.27-7.30 (m, 2H), 7.06-7.11 (m, 3H), 6.97-7.00 (m, 2H), 4.71 (t, J=7.2Hz, 1H), 3.95-4.08 (4, 2H), 3.92 (s, 3H), 2.80-3.50 (m, 4H), 1.38-1.44(m, 3H).

(S)-4-[2-(2-Ethylthiazol-4-yl)-2-(1-methyl-1H-imidazol-4-sulfonamido)ethyl]-phenylsulfamicacid: ¹H NMR (300 MHz, MeOH-d₄) δ 7.54 (s, 1H, 7.20 (s, 1H), 7.09 (s,1H), 6.92-7.00 (m, 4H), 4.62 (t, J=5.4 Hz, 1H), 3.70 (s, 3H), 2.98-3.14(m, 3H), 2.79 (dd, J=9.3 and 15.0 Hz, 1H), 1.39 (q, J=7.5 Hz, 3H).

4-{(S)-2-[2-(Thiophen-2-yl)thiazol-4-yl]-2-(2,2,2-trifluoroethylsulfonamido)-ethyl}phenylsulfamicacid: ¹H NMR (CD₃OD): δ 7.62-7.56 (m, 2H), 7.22 (s, 1H), 7.16-7.06 (m,5H), 4.84 (t, 1H, J=7.6 Hz), 3.71-3.62 (m, 2H), 3.32-3.03 (m, 2H).

{4-(S)-[2-(Phenylethanesulfonylamino)-2-(2thiophen-2-ylthiazol-4-yl)ethyl]-phenyl}sulfamicacid: ¹H NMR (300 MHz, MeOH-d₄) δ 7.56-7.62 (m, 2H), 7.04-7.19 (m, 9H),6.94-6.97 (m, 2H), 4.78 (t, J=7.8 Hz, 1H), 3.22-3.30 (m, 2H)), 3.11 (dd,J=13.5 and 7.8 Hz, 1H), 2.78-2.87 (m, 4H).

{4-(S)-[3-(Phenylpropanesulfonylamino)-2-(2thiophen-2-ylthiazol-4-yl)ethyl]-phenyl}sulfamicacid: ¹H NMR (300 MHz, MeOH-d₄) δ 7.56-7.62 (m, 2H), 6.99-7.17 (m, 10H),4.72 (t, J=7.8 Hz, 1H), 3.21 (dd, J=13.5 and 7.2 Hz, 1H), 3.02 (dd,J=13.5 and 7.2 Hz, 1H), 2.39-2.64 (m, 4H), 1.65-1.86 (m, 2H).

(S)-{4-[2-(4-Methyl-3,4-dihydro-2H-benzo[1,4]oxazine-7-sulfonylamino)-2-(2-thiophen-2-ylthiazol-4-yl)ethyl]phenyl}sulfamicacid: ¹H NMR (300 MHz, MeOH-d₄) δ 7.53 (d, J=5.1 Hz, 1H) 7.48 (d, J=5.1Hz, 1H), 7.13-7.10 (m, 1H), 7.04 (d, J=8.4 Hz, 2H), 6.93-6.88 (m, 3H),6.75 (d, J=8.1 Hz, 1H), 6.54 (d, J=8.1 Hz, 1H), 4.61 (t, J=7.5 Hz, 1H),4.20-4.08 (m, 2H), 3.14-3.00 (m, 4H), 2.69 (s, 3H).

4-{(S)-2-(4-acetamidophenylsulfonamido)-2-[2-(thiophen-2-yl)thiazol-4-yl]ethyl}phenylsulfamicacid: ¹H NMR (CD₃OD): δ 7.67-7.52 (m, 6H), 7.24-7.23 (m, 1H), 7.12-7.09(m, 3H), 7.02-6.99 (m, 2H), 4.70 (t, 1H, J=7.3 Hz), 3.25-3.00 (m, 2H),2.24 (s, 3H).

The first aspect of Category IX of the present disclosure relates tocompounds having the formula:

wherein R¹ is a substituted or unsubstituted heteroaryl and R⁴ is C₁-C₆linear, branched, or cyclic alkyl as further described herein below inTable XVII.

TABLE XVII No. R⁴ R¹ Q698 —CH₃ 4-(methoxycarbonyl)thiazol-5-yl Q699 —CH₃4-[(2-methoxy-2-oxoethyl)carbamoyl]thiazol-5-yl Q700 —CH₃5-[1-N-(2-methoxy-2-oxoethyl)-1-H-indol-3-yl]oxazol-2-yl Q701 —CH₃5-(2-methoxyphenyl)oxazol-2-yl Q702 —CH₃5-[(S)-1-(tert-butoxycarbonyl)-2-phenylethyl]oxazol-2-yl Q703 —CH₃5-[4-(methylcarboxy)phenyl]oxazol-2-yl Q704 —CH₃5-(3-methoxybenzyl)oxazol-2-yl Q705 —CH₃ 5-(4-phenyl)oxazol-2-yl Q706—CH₃ 5-(2-methoxyphenyl)thiazol-2-yl Q707 —CH₃5-(3-methoxyphenyl)thiazol-2-yl Q708 —CH₃ 5-(4-fluorophenyl)thiazol-2-ylQ709 —CH₃ 5-(2,4-difluorophenyl)thiazol-2-yl Q710 —CH₃5-(3-methoxybenzyl)thiazol-2-yl Q711 —CH₃4-(3-methoxyphenyl)thiazol-2-yl Q712 —CH₃ 4-(4-fluorophenyl)thiazol-2-ylQ713 —CH₂CH₃ 4-(methoxycarbonyl)thiazol-5-yl Q714 —CH₂CH₃4-[(2-methoxy-2-oxoethyl)carbamoyl]thiazol-5-yl Q715 —CH₂CH₃5-[1-N-(2-methoxy-2-oxoethyl)-1-H-indol-3-yl]oxazol-2-yl Q716 —CH₂CH₃5-(2-methoxyphenyl)oxazol-2-yl Q717 —CH₂CH₃5-[(S)-1-(tert-butoxycarbonyl)-2-phenylethyl]oxazol-2-yl Q718 —CH₂CH₃5-[4-(methylcarboxy)phenyl]oxazol-2-yl Q719 —CH₂CH₃5-(3-methoxybenzyl)oxazol-2-yl Q720 —CH₂CH₃ 5-(4-phenyl)oxazol-2-yl Q721—CH₂CH₃ 5-(2-methoxyphenyl)thiazol-2-yl Q722 —CH₂CH₃5-(3-methoxyphenyl)thiazol-2-yl Q723 —CH₂CH₃5-(4-fluorophenyl)thiazol-2-yl Q724 —CH₂CH₃5-(2,4-difluorophenyl)thiazol-2-yl Q725 —CH₂CH₃5-(3-methoxybenzyl)thiazol-2-yl Q726 —CH₂CH₃4-(3-methoxyphenyl)thiazol-2-yl Q727 —CH₂CH₃4-(4-fluorophenyl)thiazol-2-yl Q728 cyclopropyl4-(methoxycarbonyl)thiazol-5-yl Q729 cyclopropyl4-[(2-methoxy-2-oxoethyl)carbamoyl]thiazol-5-yl Q730 cyclopropyl5-[1-N-(2-methoxy-2-oxoethyl)-1-H-indol-3-yl]oxazol-2-yl Q731cyclopropyl 5-(2-methoxyphenyl)oxazol-2-yl Q732 cyclopropyl5-[(S)-1-(tert-butoxycarbonyl)-2-phenylethyl]oxazol-2-yl Q733cyclopropyl 5-[4-(methylcarboxy)phenyl]oxazol-2-yl Q734 cyclopropyl5-(3-methoxybenzyl)oxazol-2-yl Q735 cyclopropyl 5-(4-phenyl)oxazol-2-ylQ736 cyclopropyl 5-(2-methoxyphenyl)thiazol-2-yl Q737 cyclopropyl5-(3-methoxyphenyl)thiazol-2-yl Q738 cyclopropyl5-(4-fluorophenyl)thiazol-2-yl Q739 cyclopropyl5-(2,4-difluorophenyl)thiazol-2-yl Q740 cyclopropyl5-(3-methoxybenzyl)thiazol-2-yl Q741 cyclopropyl4-(3-methoxyphenyl)thiazol-2-yl Q742 cyclopropyl4-(4-fluorophenyl)thiazol-2-yl

Compounds according to the first aspect of Category IX which comprise asubstituted or unsubstituted thiazol-4-yl unit for R¹ can be prepared bythe procedure outlined in Scheme XVII and described herein below inExample 18.

EXAMPLE 18(S)-4-(2-(2-Phenylthiazol-4-yl)2-(4-(methoxycarbonyl)thiazole-5-ylamino)ethyl)phenylsulfamicacid (45)

Preparation of (S)-2-(4-nitrophenyl)-1-(2-phenylthiazol-4-yl)ethanaminehydrobromide salt (42): A mixture of (S)-tert-butyl4-bromo-1-(4-nitrophenyl)-3-oxobutan-2-ylcarbamate, 7, (1.62 g, 4.17mmol) and thiobenzamide (0.63 g, 4.60 mmol) in CH₃CN (5 mL) is refluxedfor 24 hours. The reaction mixture is cooled to room temperature anddiethyl ether (50 mL) is added to the solution. The precipitate whichforms is collected by filtration. The solid is dried under vacuum toafford 1.2 g (67% yield) of the desired product. LC/MS ESI+ 326 (M+1).

Preparation of(S)-4-(1-isothiocyanato-2-(4-nitrophenyl)ethyl)-2-phenylthiazole (43):To a solution of(S)-2-(4-nitrophenyl)-1-(2-phenylthiazol-4-yl)ethanamine hydrobromidesalt, 42, (726 mg, 1.79 mmol) and CaCO₃ (716 mg, 7.16 mmol) in H₂O (2mL) is added CCl₄ (3 mL) followed by thiophosgene (0.28 mL, 3.58 mmol).The reaction is stirred at room temperature for 18 hours then dilutedwith CH₂Cl₂ and water. The layers are separated and the aqueous layerextracted with CH₂Cl₂. The combined organic layers are washed withbrine, dried (Na₂SO₄) and concentrated in vacuo to a residue which ispurified over silica (CH₂Cl₂) to afford 480 mg (73%) of the desiredproduct as a yellow solid. ¹H NMR (300 MHz, CDCl₃) δ 8.15 (d, J=8.7 Hz,2H), 7.97-7.99 (m, 2H), 7.43-7.50 (m, 3H), 7.34 (d, J=8.7 Hz, 2H), 7.15(d, J=0.9 Hz, 1H), 5.40-5.95 (m, 1H), 3.60 (dd, J=13.8 and 6.0 Hz, 1H),3.46 (dd, J=13.8 and 6.0 Hz).

Preparation of (S)-methyl5-[1-(2-phenylthiazol-4-yl)-2-(4-nitrophenyl)-ethylamino]thiazole-4-carboxylate(44): To a suspension of potassium tert-butoxide (89 mg, 0.75 mmol) inTHF (3 mL) is added methyl isocyanoacetate (65 μL, 0.68 mmol) followedby (S)-2-phenyl-4-(1-isothiocyanato-2-(4-nitrophenyl)ethyl)thiazole, 43,(250 mg, 0.68 mmol). The reaction mixture is stirred at room temperaturefor 2 hours then poured into sat. NaHCO₃. The mixture is extracted withEtOAc (3×25 mL) and the combined organic layers are washed with brineand dried (Na₂SO₄) and concentrated in vacuo. The crude residue ispurified over silica to afford 323 mg (˜100% yield) of the desiredproduct as a slightly yellow solid. ¹H NMR (300 MHz, CDCl₃) δ 8.09-8.13(m, 2H), 7.95-7.98 (m, 3H), 7.84 (d, J=1.2 Hz, 1H), 7.44-7.50 (m, 3H),7.28-7.31 (m, 2H), 7.96 (d, J=0.6 Hz, 1H), 4.71-4.78 (m, 1H), 3.92 (s,3H), 3.60 (dd, J=13.8 and 6.0 Hz, 1H), 3.45 (dd, J=13.8 and 6.0 Hz, 1H).

Preparation of(S)-4-(2-(2-phenylthiazol-4-yl)2-(4-(methoxycarbonyl)thiazole-5-ylamino)ethyl)phenylsulfamicacid (45): (S)-methyl5-[1-(2-phenylthiazol-4-yl)-2-(4-nitrophenyl)-ethylamino]thiazole-4-carboxylate,44, (323 mg, 0.68 mmol) and tin (II) chloride (612 mg, 2.72 mmol) aredissolved in EtOH and the solution is brought to reflux. The solvent isremoved in vacuo and the resulting residue is dissolved in EtOAc. Asaturated solution of NaHCO₃ is added and the solution is stirred 1hour. The organic layer is separated and the aqueous layer extractedtwice with EtOAc. The combined organic layers are dried (Na₂SO₄),filtered and concentrated to a residue which is dissolved in pyridine(10 mL) and treated with SO₃-pyridine (130 mg, 0.82 mmol). The reactionis stirred at room temperature for 5 minutes after which a 7% solutionof NH₄OH is added. The mixture is then concentrated and the resultingresidue is purified by reverse phase chromatography to afford 0.071 g ofthe desired product as the ammonium salt ¹H NMR (300 MHz, MeOH-d₄) δ7.97-8.00 (m, 3H), 7.48-7.52 (m, 3H), 7.22 (s, 1H), 7.03-7.13 (m, 4H),4.74 (t, J=6.6 Hz, 1H), 3.88 (s, 3H), 3.28-3.42 (m, 2H).

Compounds according to the first aspect of Category IX which comprise asubstituted or unsubstituted thiazol-2-yl unit for R¹ can be prepared bythe procedure outlined in Scheme XVIII and described herein below inExample 19. Intermediate 46 can be prepared according to Scheme II andExample 2 by substituting cyclopropane-carbothioic acid amide forthiophen-2-carbothioic acid amide.

EXAMPLE 194-{(S)-2-(2-Cyclopropylthiazol-4-yl)-2-[4-(3-methoxyphenyl)thiazol-2-ylamino]ethyl}phenylsulfamicacid (50)

Preparation of(S)-1-(1-(2-cyclopropylthiazol-4-yl)-2-(4-nitrophenyl)ethyl)-thiourea(47): To a solution of(S)-1-(2-cyclopropylthiazol-4-yl)-2-(4-nitrophenyl)ethan-aminehydrobromide hydrobromide salt, 32, (4.04 g, 10.9 mmol) and CaCO₃ (2.18g, 21.8 mmol) in CCl₄/water (25 mL/20 mL) is added thiophosgene (1.5 g,13.1 mmol). The reaction is stirred at room temperature for 18 hoursthen diluted with CH₂Cl₂ and water. The layers are separated and theaqueous layer extracted with CH₂Cl₂. The combined organic layers arewashed with brine, dried (Na₂SO₄) and concentrated in vacuo to a residuewhich is subsequently treated with ammonia (0.5M in 1,4-dioxane, 120 mL)which is purified over silica to afford 2.90 g of the desired product asa red-brown solid. LC/MS ESI− 347 (M−1).

Preparation of(S)-4-(3-methoxybenzyl)-N-(1-(2-cyclopropylthiazol-4-yl)-2-(4-nitrophenyl)ethyl)thiazol-2-amine(48):(S)-1-(1-(2-Cyclopropylthiazol-4-yl)-2-(4-nitrophenyl)ethyl)-thiourea,47, (350 mg, 1.00 mmol) and 2-bromo-3′-methoxy-acetophenone (253 mg,1.10 mmol) are combined in 3 mL CH₃CN and heated to reflux for 24 hours.The mixture is concentrated and chromatographed to afford 0.172 g of theproduct as a yellow solid. LC/MS ESI+ 479 (M+1).

Preparation of4-{(S)-2-(2-cyclopropylthiazol-4-yl)-2-[4-(3-methoxyphenyl)-thiazol-2-ylamino]ethyl}phenylsulfamicacid (49):(S)-4-(3-methoxybenzyl)-N-(1-(2-cyclopropylthiazol-4-yl)-2-(4-nitrophenyl)ethyl)thiazol-2-amine,48, (0.172 g) is dissolved in 10 mL MeOH. A catalytic amount of Pd/C(10% w/w) is added and the mixture is stirred under a hydrogenatmosphere for 18 hours. The reaction mixture is filtered through a bedof CELITE™ and the solvent is removed under reduced pressure. The crudeproduct is dissolved in 5 mL pyridine and treated with SO₃-pyridine (114mg). The reaction is stirred at room temperature for 5 minutes afterwhich 10 mL of a 7% solution of NH₄OH is added. The mixture is thenconcentrated and the resulting residue is purified by reverse-phasechromatography to afford 0.033 g of the desired product as the ammoniumsalt. ¹H NMR (CD₃OD): δ 7.33-7.22 (m, 3H), 7.10-6.97 (m, 5H), 6.84-6.80(m, 2H), 5.02 (t, 1H, J=6.9 Hz), 3.82 (s, 1H), 3.18 (q, 2H, J=7.1 Hz),2.36 (q, 1H, J=4.6 Hz), 1.20-1.13 (m, 2H), 1.04-0.99 (m, 2H).

The following are non-limiting examples of compounds encompassed withinthe first aspect of Category IX.

(S)-4-(2-(4-((2-Methoxy-2-oxoethyl)carbamoyl)thiazole-5-ylamino)2-(2-ethylthiazole-4-yl)ethyl)phenylsulfamicacid: ¹H NMR (300 MHz, MeOH-d₄) δ 7.91 (s, 1H), 7.08-7.10 (m, 3H), 6.99(d, J=8.7 Hz, 2H), 4.58 (t, J=6.9 Hz, 1H), 4.11 (d, J=2.7 Hz, 2H), 3.78(s, 3H), 3.14-3.28 (m, 2H), 3.06 (q, J=7.5 Hz, 2H), 1.41 (t, J=7.5 Hz,3H).

(S)-4-(2-{5-[1-N-(2-Methoxy-2-oxoethylcarbamoyl)-1-H-indol-3-yl]oxazol-2-ylamino}-2-(2-methylthiazol-4-yl)ethyl)phenylsulfamicacid: ¹H NMR (300 MHz, MeOH-d₄) δ 7.63 (d, J=7.8 Hz, 1H), 7.37 (s, 1H),7.18-7.29 (m, 4H), 7.02-7.16 (m, 4H), 6.85 (s, 1H), 5.04-5.09 (m, 1H),4.85 (s, 3H), 3.27 (dd, J=13.5 and 8.1 Hz, 1H), 3.10 (m, J=13.5 and 8.1Hz, 1H), 2.69 (s, 3H).

4-((S)-2-(5-(2-Methoxyphenyl)oxazol-2-ylamino)-2-(2-methylthiazol-4-yl)ethyl)phenylsulfamicacid: ¹H NMR (300 MHz, MeOH-d₄) δ 7.52 (dd, J=7.5 and 1.2 Hz, 1H),6.95-7.24 (m, 10H), 5.04-5.09 (m, 1H), 3.92 (s, 3H), 3.26 (dd, J=13.8and 8.4 Hz, 1H), 3.10 (dd, J=13.8 and 8.4 Hz, 1H), 2.72 (s, 3H).

4-((S)-2-(5-((S)-1-(tert-Butoxycarbonyl)-2-phenylethyl)oxazole-2-ylamino)-2-(2-methylthiazole-4-yl)ethyl)phenylsulfamicacid: ¹H NMR (300 MHz, MeOH-d₄) δ 7.03-7.27 (m, 10 H), 6.50 (s, 1H),4.95-5.00 (m, 1H), 4.76 (t, J=6.9 Hz, 1H), 3.22 (dd, J=14.1 and 6.9 Hz,1H), 3.00-3.10 (m, 2H), 2.90 (dd, J=14.1 and 6.9 Hz, 1H), 2.72 (s, 3H),1.37 (s, 9H).

(S)-{4-{2-[5-(4-Methoxycarbonyl)phenyl]oxazol-2-ylamino}-2-(2-methylthiazol-4-yl)ethyl}phenylsulfamicacid: ¹H NMR (300 MHz, MeOH-d₄) δ 7.99 (d, J=7.5 Hz, 2H), 7.56-7.59 (m,2H), 7.23-7.24 (m, 1H), 7.08-7.14 (m, 4H), 6.83 (d, J=10.2 Hz, 1H), 5.08(t, J=6.0 Hz, 1H), 3.91 (s, 3H), 3.25-3.35 (m, 1H), 3.09-3.13 (m, 1H),2.73 (s, 3H).

(S)-4-(2-(5-(3-Methoxybenzyl)oxazole-2-ylamino)-2-(2-methylthiazole-4-yl)ethyl)phenylsulfamicacid: ¹H NMR (300 MHz, MeOH-d₄) δ 7.03-7.28 (m, 8H), 6.79-6.83 (m, 1H),5.70 (s, 1H), 4.99-5.06 (m, 2H), 4.41 (d, J=2.1 Hz, 2H), 3.80 (s, 3H),3.27-3.37 (m, 1H), 3.03-3.15 (m, 1H), 2.71 (s, 3H).

(S)-4-(2-(2-Methylthiazole-4-yl)2-(5-phenyloxazole-2-ylamino)ethyl)phenyl-sulfamicacid: ¹H NMR (300 MHz, MeOH-d₄) δ 7.45 (d, J=8.7 Hz, 2H), 7.33 (t, J=7.8Hz, 2H), 7.18-7.22 (m, 1H), 7.10-7.14 (m, 6H), 7.04 (s, 1H), 5.04-5.09(m, 1H), 3.26 (dd, J=13.8 and 6.3 Hz, 1H), 3.10 (dd, J=13.8 and 6.3 Hz,1H), 2.70 (s, 3H).

4-((S)-2-(2-Cyclopropylthiazol-4-yl)-2-(4-(3-methoxyphenyl)thiazol-2-ylamino)-ethyl)phenylsulfamicacid: ¹H NMR (CD₃OD): δ 7.33-7.22 (m, 3H), 7.10-6.97 (m, 5H), 6.84-6.80(m, 2H), 5.02 (t, 1H, J=6.9 Hz), 3.82 (s, 1H), 3.18 (q, 2H, J=7.1 Hz),2.36 (q, 1H, J=4.6 Hz), 1.20-1.13 (m, 2H), 1.04-0.99 (m, 2H).

(S)-4-(2-(2-cyclopropylthiazol-4-yl)-2-(4-(4-fluorophenyl)thiazol-2-ylamino)ethyl)-phenylsulfamicacid: ¹H NMR (CD₃OD): δ 7.79-7.74 (m, 2H), 7.14-7.03 (m, 7H), 7.21 (s,1H), 6.79 (s, 1H), 5.08 (t, 1H, J=6.6 Hz), 3.29-3.12 (m, 2H), 2.40 (q,2.40, J=5.1 Hz), 1.23-1.18 (m, 2H), 1.08-1.02 (m, 2H).

4-((S)-2-(2-cyclopropylthiazol-4-yl)-2-(4-(2-methoxyphenyl)thiazol-2-ylamino)-ethyl)phenylsulfamicacid: ¹H NMR (CD₃OD): δ 7.89-7.87 (d, 1H, J=7.6 Hz), 7.28 (t, 1H, J=7.0Hz), 7.10-6.96 (m, 8H), 5.03 (t, 1H, J=6.9 Hz), 3.90 (s, 1H), 3.19 (q,2H, J=6.6 Hz), 2.38 (q, 1H, J=4.8 Hz), 1.21-1.14 (m, 2H), 1.06-1.00 (m,2H).

4-((S)-2-(2-cyclopropylthiazol-4-yl)-2-(4-(2,4-difluorophenyl)thiazol-2-ylamino)-ethyl)phenylsulfamicacid: ¹H NMR (CD₃OD): δ 8.06-8.02 (q, 2H, J=6.9 Hz), 7.12-6.95 (m, 7H),6.88 (s, 1H), 5.11 (t, 1H, J=6.9 Hz), 3.22-3.15 (m, 2H), 2.38 (q, 1H,J=4.8 Hz), 1.22-1.15 (m, 2H), 1.06-1.02 (m, 2H).

(S)-4-(2-(4-(3-methoxybenzyl)thiazol-2-ylamino)-2-(2-cyclopropylthiazol-4-yl)ethyl)phenylsulfamicacid: ¹H NMR (CD₃OD): δ 7.22-7.17 (m, 3H), 7.09-6.97 (m, 5H), 6.78-6.66(m, 3H), 3.77 (s, 2H), 3.75 (s, 3H), 3.20-3.07 (m, 2H), 2.35 (q, 1H,J=4.8 Hz), 1.19-1.13 (m, 2H), 1.03-1.00 (m, 2H).

(S)-{5-[1-(2-Ethylthiazol-4-yl)-2-(4-sulfoaminophenyl)ethylamino]-2-methyl-2H-[1,2,4]triazole-3-yl}carbamicacid methyl ester: ¹H NMR (300 MHz, MeOH-d₄) δ 6.97-7.08 (m, 5H), 3.71(s, 3H), 3.51 (s, 3H), 3.15 (dd, J=13.5 and 6.3 Hz, 1H), 3.02-3.07 (m,3H), 1.40 (t, J=6.6 Hz, 3H).

The second aspect of Category V of the present disclosure relates tocompounds having the formula:

wherein R¹ is a substituted or unsubstituted heteroaryl and R⁴ issubstituted or unsubstituted phenyl and substituted or unsubstitutedheteroaryl as further described herein below in Table XVIII.

TABLE XVIII No. R⁴ R¹ R743 phenyl 4-(methoxycarbonyl)thiazol-5-yl R744phenyl 4-[(2-methoxy-2-oxoethyl)carbamoyl]thiazol-5-yl R745 phenyl5-[1-N-(2-methoxy-2-oxoethyl)-1-H-indol-3-yl]oxazol-2-yl R746 phenyl5-(2-methoxyphenyl)oxazol-2-yl R747 phenyl5-[(S)-1-(tert-butoxycarbonyl)-2-phenylethyl]oxazol-2-yl R748 phenyl5-[4-(methylcarboxy)phenyl]oxazol-2-yl R749 phenyl5-(3-methoxybenzyl)oxazol-2-yl R750 phenyl 5-(4-phenyl)oxazol-2-yl R751phenyl 5-(2-methoxyphenyl)thiazol-2-yl R752 phenyl5-(3-methoxyphenyl)thiazol-2-yl R753 phenyl5-(4-fluorophenyl)thiazol-2-yl R754 phenyl5-(2,4-difluorophenyl)thiazol-2-yl R755 phenyl5-(3-methoxybenzyl)thiazol-2-yl R756 phenyl4-(3-methoxyphenyl)thiazol-2-yl R757 phenyl4-(4-fluorophenyl)thiazol-2-yl R758 thiophen-2-yl4-(methoxycarbonyl)thiazol-5-yl R759 thiophen-2-yl4-[(2-methoxy-2-oxoethyl)carbamoyl]thiazol-5-yl R760 thiophen-2-yl5-[1-N-(2-methoxy-2-oxoethyl)-1-H-indol-3-yl]oxazol-2-yl R761thiophen-2-yl 5-(2-methoxyphenyl)oxazol-2-yl R762 thiophen-2-yl5-[(S)-1-(tert-butoxycarbonyl)-2-phenylethyl]oxazol-2-yl R763thiophen-2-yl 5-[4-(methylcarboxy)phenyl]oxazol-2-yl R764 thiophen-2-yl5-(3-methoxybenzyl)oxazol-2-yl R765 thiophen-2-yl5-(4-phenyl)oxazol-2-yl R766 thiophen-2-yl5-(2-methoxyphenyl)thiazol-2-yl R767 thiophen-2-yl5-(3-methoxyphenyl)thiazol-2-yl R768 thiophen-2-yl5-(4-fluorophenyl)thiazol-2-yl R769 thiophen-2-yl5-(2,4-difluorophenyl)thiazol-2-yl R770 thiophen-2-yl5-(3-methoxybenzyl)thiazol-2-yl R771 thiophen-2-yl4-(3-methoxyphenyl)thiazol-2-yl R772 thiophen-2-yl4-(4-fluorophenyl)thiazol-2-yl R773 cyclopropyl4-(methoxycarbonyl)thiazol-5-yl R774 cyclopropyl4-[(2-methoxy-2-oxoethyl)carbamoyl]thiazol-5-yl R775 cyclopropyl5-[1-N-(2-methoxy-2-oxoethyl)-1-H-indol-3-yl]oxazol-2-yl R776cyclopropyl 5-(2-methoxyphenyl)oxazol-2-yl R777 cyclopropyl5-[(S)-1-(tert-butoxycarbonyl)-2-phenylethyl]oxazol-2-yl R778cyclopropyl 5-[4-(methylcarboxy)phenyl]oxazol-2-yl R779 cyclopropyl5-(3-methoxybenzyl)oxazol-2-yl R780 cyclopropyl 5-(4-phenyl)oxazol-2-ylR781 cyclopropyl 5-(2-methoxyphenyl)thiazol-2-yl R782 cyclopropyl5-(3-methoxyphenyl)thiazol-2-yl R783 cyclopropyl5-(4-fluorophenyl)thiazol-2-yl R784 cyclopropyl5-(2,4-difluorophenyl)thiazol-2-yl R785 cyclopropyl5-(3-methoxybenzyl)thiazol-2-yl R786 cyclopropyl4-(3-methoxyphenyl)thiazol-2-yl R787 cyclopropyl4-(4-fluorophenyl)thiazol-2-yl

Compounds according to the second aspect of Category IX which comprise asubstituted or unsubstituted thiazol-4-yl unit for R¹ can be prepared bythe procedure outlined in Schemes XIX, XX, and XXI and described hereinbelow in Examples 20, 21, and 22.

EXAMPLE 20

(S)-4-(2-(5-Methyl-1,3,4-thiadiazol-2-ylamino)-2-(2-phenylthiazol-4-yl)ethyl)phenylsulfamicacid (55)

Preparation of [3-diazo-1-(4-nitrobenzyl)-2-oxo-propyl]-carbamic acidtert-butyl ester (50): To a 0° C. solution of2-(S)-tert-butoxycarbonylamino-3-(4-nitrophenyl)-propionic acid (1.20 g,4.0 mmol) in THF (20 mL) is added dropwise triethylamine (0.61 mL, 4.4mmol) followed by iso-butyl chloroformate (0.57 mL, 4.4 mmol). Thereaction mixture is stirred at 0° C. for 20 minutes then filtered. Thefiltrate is treated with an ether solution of diazomethane (˜16 mmol) at0° C. The reaction mixture is stirred at room temperature for 3 hoursand concentrated. The residue is dissolved in EtOAc and washedsuccessively with water and brine, dried (Na₂SO₄), filtered andconcentrated in vacuo. The resulting residue is purified over silica(hexane/EtOAc 2:1) to afford 1.1 g (82% yield) of the desired product asa slightly yellow solid. ¹H NMR (300 MHz, CDCl₃) δ 8.16 (d, J=8.7 Hz,2H), 7.39 (d, J=8.7 Hz, 2H), 5.39 (s, 1H), 5.16 (d, J=6.3 Hz, 1H), 4.49(s, 1H), 3.25 (dd, J=13.8 and 6.6, 1H), 3.06 (dd, J=13.5 and 6.9 Hz,1H), 1.41 (s, 9H).

Preparation of [3-bromo-1-(4-nitro-benzyl)-2-oxo-propyl]-carbamic acidtert-butyl ester (51): To a 0° C. solution of[3-diazo-1-(4-nitrobenzyl)-2-oxo-propyl]-carbamic acid tert-butyl ester,50, (0.350 g, 1.04 mmol) in THF (5 mL) is added dropwise 48% aq. HBr(0.14 mL, 1.25 mmol). The reaction mixture is stirred at 0° C. for 1.5hours and quenched at 0° C. with saturated aqueous Na₂CO₃. The mixtureis extracted with EtOAc (3×25 mL) and the combined organic extracts arewashed with brine, dried (Na₂SO₄), filtered and concentrated in vacuo toafford 0.400 g of the desired product that is used in the next stepwithout further purification. ¹H NMR (300 MHz, CDCl₃) δ 8.20 (d, J=8.4Hz, 2H), 7.39 (d, J=8.4 Hz, 2H), 5.06 (d, J=7.8 Hz, 1H), 4.80 (q, J=6.3Hz, 1H), 4.04 (s, 2H), 1.42 (s, 9H).

Preparation of (S)-2-(4-nitrophenyl)-1-(2-phenylthiazol-4-yl)ethanaminehydrobromide salt (52): A mixture of[3-bromo-1-(4-nitro-benzyl)-2-oxo-propyl]-carbamic acid tert-butylester, 51, (1.62 g, 4.17 mmol) and benzothioamide (0.630 g, 4.59 mmol),in CH₃CN (5 mL) is refluxed for 24 hours. The reaction mixture is cooledto room temperature and diethyl ether (50 mL) is added to the solutionand the precipitate that forms is collected by filtration. The solid isdried under vacuum to afford 1.059 g (63%) of the desired product. ESI+MS 326 (M+1).

Preparation of(S)-4-[1-isothiocyanato-2-(4-nitrophenyl)-ethyl]-2-phenylthiazole (53):To a solution of(S)-2-(4-nitrophenyl)-1-(2-phenylthiazol-4-yl)ethanamine hydrobromidesalt, 52, (2.03 g, 5 mmol) and CaCO₃ (1 g, 10 mmol) in CCl₄/water(10:7.5 mL) is added thiophosgene (0.46 mL, 6 mmol). The reaction isstirred at room temperature for 18 hours then diluted with CH₂Cl₂ andwater. The layers are separated and the aqueous layer extracted withCH₂Cl₂. The combined organic layers are washed with brine, dried(Na₂SO₄) and concentrated in vacuo to a residue that is purified oversilica (CH₂Cl₂) to afford 1.71 g (93% yield) of the desired product.ESI+ MS 368 (M+1).

Preparation of(S)-5-methyl-N-[2-(4-nitrophenyl)-1-(2-phenylthiazol-4-yl)ethyl]-1,3,4-thiadiazol-2-amine(54): A solution of(S)-4-[1-isothiocyanato-2-(4-nitrophenyl)-ethyl]-2-phenylthiazole, 53,(332 mg, 0.876 mmol) and acetic hydrazide (65 mg, 0.876 mmol) in EtOH (5mL) is refluxed for 2 hours. The solvent is removed under reducedpressure, the residue is dissolved in POCl₃ (3 mL) and the resultingsolution is stirred at room temperature for 18 hours after which thesolution is heated to 50° C. for 2 hours. The solvent is removed invacuo and the residue is dissolved in EtOAc (40 mL) and the resultingsolution is treated with 1N NaOH until the pH remains approximately 8.The solution is extracted with EtOAc. The combined aqueous layers arewashed with EtOAc, the organic layers combined, washed with brine, driedover MgSO₄, filtered, and concentrated in vacuo to afford 0.345 g (93%yield) of the desired product as a yellow solid. ¹H NMR (CDCl₃) 8.09 (d,J=8.4 Hz, 2H), 7.91 (m, 2H), 7.46 (m, 4H), 7.44 (s, 1H), 5.23 (m, 1H),3.59 (m, 2H), 2.49 (s, 3H). ESI+ MS 424 (M+1).

Preparation of(S)-4-[2-(5-methyl-1,3,4-thiadiazol-2-ylamino)-2-(2-phenylthiazol-4-yl)ethyl]phenylsulfamicacid (55):(S)-5-Methyl-N-[2-(4-nitrophenyl)-1-(2-phenylthiazol-4-yl)ethyl]-1,3,4-thiadiazol-2-amine,54, (0.404 g, 0.954 mmol) is dissolved in MeOH (5 mL). Pd/C (50 mg, 10%w/w) is added and the mixture is stirred under a hydrogen atmosphereuntil the reaction is judged to be complete. The reaction mixture isfiltered through a bed of CELITE™ and the solvent removed under reducedpressure. The crude product is dissolved in pyridine (4 mL) and treatedwith SO₃-pyridine (0.304 g, 1.91 mmol). The reaction is stirred at roomtemperature for 5 minutes after which a 7% solution of NH₄OH (50 mL) isadded. The mixture is then concentrated and the resulting residue ispurified by reverse phase preparative HPLC to afford 0.052 g (11% yield)of the desired product as the ammonium salt. ¹H NMR (CD₃OD): δ 8.00-7.97(m, 2H), 7.51-7.47 (m, 3H), 7.23 (s, 1H), 7.11-7.04 (q, 4H, J=9.0 Hz),5.18 (t, 1H, J=7.2 Hz), 3.34-3.22 (m, 2H), 2.50 (s, 3H). ESI− MS 472(M−1).

EXAMPLE 214-{(S)-2-[4-(2-Methoxyphenyl)thiazol-2-ylamino)-2-[2-(thiophen-2-yl)thiazol-4-yl]ethyl}phenylsulfamicacid (58)

Preparation of(S)-1-[1-(thiophen-2-ylthiazol-4-yl)-2-(4-nitrophenyl)ethyl]-thiourea(56): To a solution of(S)-2-(4-nitrophenyl)-1-(thiophen-2-ylthiazol-4-yl)ethanaminehydrobromide salt, 8, (1.23 g, 2.98 mmol) and CaCO₃ (0.597 g, 5.96 mmol)in CCl₄/water (10 mL/5 mL) is added thiophosgene (0.412 g, 3.58 mmol).The reaction is stirred at room temperature for 18 hours then dilutedwith CH₂Cl₂ and water. The layers are separated and the aqueous layerextracted with CH₂Cl₂. The combined organic layers are washed withbrine, dried (Na₂SO₄) and concentrated in vacuo to a residue which issubsequently treated with ammonia (0.5M in 1,4-dioxane, 29.4 mL, 14.7mmol) which is purified over silica to afford 0.490 g of the desiredproduct as a red-brown solid. ESI+ MS 399 (M+1).

Preparation of4-(2-methoxyphenyl)-N-{(S)-2-(4-nitrophenyl)-1-[2-(thiophen-2-yl)thiazol-4-yl]ethyl}thiazol-2-amine(57):(S)-1-[1-(thiophen-2-ylthiazol-4-yl)-2-(4-nitrophenyl)ethyl]-thiourea,56, (265 mg, 0.679 mmol) is treated with bromo-2′-methoxyacetophenone(171 mg, 0.746 mmol) to afford 0.221 g of the product as a yellow solid.ESI+ MS 521 (M+1).

Preparation on4-{(S)-2-[4-(2-methoxyphenyl)thiazol-2-ylamino)-2-[2-(thiophen-2-yl)thiazol-4-yl]ethyl}phenylsulfamicacid (58):4-(2-methoxyphenyl)-N-{(S)-2-(4-nitrophenyl)-1-[2-(thiophen-2-yl)thiazol-4-yl]ethyl}thiazol-2-amine,57, (0.229 g) is dissolved in 12 mL MeOH. A catalytic amount of Pd/C(10% w/w) is added and the mixture is stirred under a hydrogenatmosphere for 18 hours. The reaction mixture is filtered through a bedof CELITE™ and the solvent is removed under reduced pressure. The crudeproduct is dissolved in 6 mL pyridine and treated with SO₃-pyridine (140mg). The reaction is stirred at room temperature for 5 minutes afterwhich 10 mL of a 7% solution of NH₄OH is added. The mixture is thenconcentrated and the resulting residue is purified by reverse-phasechromatography to afford 0.033 g of the desired product as the ammoniumsalt. ¹H NMR (CD₃OD): δ 7.96-7.93 (m, 1H), 7.60-7.55 (m, 2H), 7.29-7.23(m, 1H), 7.18-6.95 (m, 9H), 5.15 (t, 1H, J=6.9 Hz), 3.90 (s, 3H),3.35-3.24 (m, 2H).

Compounds according to the second aspect of Category IX which comprise asubstituted or unsubstituted oxazol-2-yl unit for R¹ can be prepared bythe procedure outlined in Scheme XXI and described herein below inExample 22. Intermediate 39 can be prepared according to Scheme XVII andExample 18.

EXAMPLE 224-{(S)-2-[5-(3-Methoxyphenyl)oxazole-2-ylamino]-2-(2-phenylthiazol-4-yl)ethyl}phenylsulfamicacid (61)

Preparation of[5-(3-methoxyphenyl)oxazol-2-yl]-[2-(4-nitrophenyl)-1-(2-phenylthiazole-4-yl)ethyl]amine(60): A mixture of(S)-4-(isothiocyanato-2-(4-nitrophenyl)ethyl)-2-phenylthiazole, 53, (300mg, 0.81 mmol), 1-azido-1-(3-methoxyphenyl)ethanone (382 mg, 2.0 mmol)and PPh₃ (0.8 g, polymer bound, ˜3 mmol/g) in dioxane (6 mL) is heatedat 90° C. for 20 minutes. The reaction solution is cooled to roomtemperature and the solvent removed in vacuo and the resulting residueis purified over silica to afford 300 mg (74% yield) of the desiredproduct as a yellow solid. ¹H NMR (300 MHz, MeOH-d₄) δ 8.02 (d, J=7.2Hz, 2H), 7.92-7.99 (m, 2H), 7.42-7.47 (m, 3H), 7.22-7.27 (m, 3H),6.69-7.03 (m, 4H), 6.75-6.78 (m, 1H), 5.26 (t, J=6.3 Hz, 1H), 3.83 (s,4H), 3.42-3.45 (m, 2H).

Preparation of4-{(S)-2-[5-(3-methoxyphenyl)oxazole-2-ylamino]-2-(2-phenylthiazole-4-yl)ethyl}phenylsulfamicacid (61):[5-(3-methoxyphenyl)oxazol-2-yl]-[2-(4-nitrophenyl)-1-(2-phenylthiazole-4-yl)ethyl]amine,60, (300 mg, 0.60 mmol) is dissolved in MeOH (15 mL). A catalytic amountof Pd/C (10% w/w) is added and the mixture is stirred under a hydrogenatmosphere 18 hours. The reaction mixture is filtered through a bed ofCELITE™ and the solvent is removed under reduced pressure. The crudeproduct is dissolved in pyridine (10 mL) and treated with SO₃-pyridine(190 mg, 1.2 mmol). The reaction is stirred at room temperature for 5minutes after which a 7% solution of NH₄OH is added. The mixture is thenconcentrated and the resulting residue is purified by reverse-phasechromatography to afford 0.042 g of the desired product as the ammoniumsalt. ¹H NMR (300 MHz, MeOH-d₄) δ 7.99 (d, J=7.5 Hz, 2H), 7.46-7.50 (m,3H), 7.23-7.29 (m, 3H), 7.04-7.12 (m, 6H), 6.78 (dd, J=8.4 and 2.4 Hz,1H), 5.16 (t, J=6.6 Hz, 1H), 3.81 (s, 3H), 3.29-3.39 (m, 1H), 3.17 (dd,J=13.8 and 8.1 Hz, 1H).

The following are non-limiting examples of the second aspect of CategoryIX of the present disclosure.

(S)-4-(2-(5-Phenyl-1,3,4-thiadiazol-2-ylamino)-2-(2-phenylthiazol-4-yl)ethyl)-phenylsulfamicacid: ¹H NMR (CD₃OD): δ 7.97-7.94 (m, 2H), 7.73-7.70 (m, 2H), 7.44-7.39(m, 6H), 7.25 (s, 1H), 7.12 (s, 4H), 5.29 (t, 1H, J=6.9 Hz), 3.35-3.26(m, 2H).

4-((S)-2-(5-Propyl-1,3,4-thiadiazol-2-ylamino)-2-(2-(thiophen-2-yl)thiazol-4-yl)ethyl)phenylsulfamicacid: ¹H NMR (CD₃OD): δ 7.59-7.54 (m, 2H), 7.17-7.03 (m, 6H), 5.13 (t,1H, J=7.2 Hz), 3.32-3.13 (m, 2H), 2.81 (t, 2H, J=7.4 Hz), 1.76-1.63 (h,6H, J=7.4 Hz), 0.97 (t, 3H, J=7.3 Hz).

4-((S)-2-(5-Benzyl-1,3,4-thiadiazol-2-ylamino)-2-(2-(thiophen-2-yl)thiazol-4-yl)ethyl)phenylsulfamicacid: ¹H NMR (CD₃OD): δ (m, 2H), 7.49-7.45 (m, 2H), 7.26-7.16 (m, 5H),7.05-6.94 (m, 6H), 5.04 (t, 1H, J=7.1 Hz), 4.07 (s, 2H), 3.22-3.04 (m,2H).

4-((S)-2-(5-(Naphthalen-1-ylmethyl)-1,3,4-thiadiazol-2-ylamino)-2-(2-(thiophen-2-yl)thiazol-4-yl)ethyl)phenylsulfamicacid: ¹H NMR (CD₃OD): δ 8.08-8.05 (m, 1H), 7.89-7.80 (m, 2H), 7.55-7.43(m, 6H), 7.11-7.00 (m, 6H), 5.08 (t, 1H, J=7.1 Hz), 4.63 (s, 2H),3.26-3.08 (m, 2H).

4-((S)-2-(5-((Methoxycarbonyl)methyl)-1,3,4-thiadiazol-2-ylamino)-2-(2-(thiophen-2-yl)thiazol-4-yl)ethyl)phenylsulfamicacid: ¹H NMR (CD₃OD): δ 7.48-7.44 (m, 2H), 7.03-6.92 (m, 6H), 5.02 (t,1H, J=7.2 Hz), 4.30 (s, 2H), 3.55 (s, 3H), 3.22-3.02 (m, 2H).

4-((S)-2-(5-((2-Methylthiazol-4-yl)methyl)-1,3,4-thiadiazol-2-ylamino)-2-(2-(thiophen-2-yl)thiazol-4-yl)ethyl)phenylsulfamicacid: ¹H NMR (CD₃OD): δ 7.60-7.56 (m, 2H), 7.19 (s, 1H), 7.15-7.12 (m,2H), 7.09-7.03 (q, 4H, J=8.7 Hz), 5.14 (t, 1H, J=7.2 Hz), 4.28 (s, 2H),3.33-3.14 (m, 2H), 2.67 (s, 3H).

4-{(S)-2-[4-(2,4-Difluorophenyl)thiazol-2-ylamino]-2-[2-(thiophen-2-yl)thiazol-4-yl]ethyl}phenylsulfamicacid: ¹H NMR (CD₃OD): δ 8.06-8.02 (q, 1H, J=6.8 Hz), 7.59-7.54 (m, 2H),7.16-7.08 (m, 6H), 7.01-6.88 (m, 4H), 5.20 (t, 1H, J=7.0 Hz), 3.36-3.17(m, 2H).

(S)-4-{2-[4-(Ethoxycarbonyl)thiazol-2-ylamino]-2-(2-phenylthiazol-4-yl)ethyl}phenylsulfamicacid: ¹H NMR (CD₃OD): δ 8.02-7.99 (m, 2H), 7.54-7.45 (m, 4H), 7.26 (s,1H), 7.08 (s, 4H), 5.26 (t, 1H, J=6.9 Hz), 4.35-4.28 (q, 2H, J=6.9 Hz),3.38-3.18 (m, 2H), 1.36 (t, 3H, J=7.2 Hz).

(S)-4-{2-[4-(2-Ethoxy-2-oxoethyl)thiazol-2-ylamino]-2-(2-phenylthiazol-4-yl)ethyl}phenylsulfamicacid: ¹H NMR (CD₃OD): δ 7.96 (m, 2H), 7.50-7.46 (m, 3H), 7.21 (s, 1H),7.10-7.04 (m, 4H), 6.37 (s, 1H), 5.09 (t, 1H, J=6.9 Hz), 4.17-4.10 (q,2H, J=7.1 Hz), 3.54 (s, 2H), 3.35-3.14 (m, 2H), 1.22 (t, 3H, J=7.1 Hz).

(S)-4-{2-[4-(4-acetamidophenyl)thiazol-2-ylamino]-2-(2-phenylthiazol-4-yl)ethyl}phenylsulfamicacid: ¹H NMR (CD₃OD): δ 8.11 (m, 2H), 7.82-7.80 (m, 2H), 7.71-7.61 (m,6H), 7.40 (s, 1H), 7.23 (s, 4H), 5.32 (t, 1H, J=7.0 Hz), 3.51-3.35 (m,2H), 2.28 (s, 3H).

(S)-4-[2-(4-phenylthiazol-2-ylamino)-2-(2-phenylthiazol-4-yl)ethyl]phenylsulfamicacid: ¹H NMR (CD₃OD): δ 8.03-7.99 (m, 2H), 7.75-7.72 (d, 2H, J=8.4 Hz),7.53-7.48 (m, 3H), 7.42 (m, 4H), 7.12 (s, 4H), 6.86 (s, 1H), 5.23 (t,1H, J=7.2 Hz), 3.40-3.27 (m, 2H).

(S)-4-{2-[4-(4-(methoxycarbonyl)phenyl)thiazol-2-ylamino]-2-(2-phenylthiazol-4-yl)ethyl}phenylsulfamicacid: ¹H NMR (CD₃OD): δ 8.04-8.00 (m, 4H), 7.92-7.89 (d, 2H, J=9.0 Hz),7.53-7.49 (m, 3H), 7.30 (s, 1H), 7.15 (s, 4H), 7.05 (s, 1H), 5.28 (t,1H, J=6.9 Hz), 3.93 (s, 3H), 3.35-3.24 (m, 2H).

4-{(S)-2-[4-(Ethoxycarbonyl)thiazol-2-ylamino]-2-[2-(thiophen-2-yl)thiazol-4-yl]ethyl}phenylsulfamicacid: ¹H NMR (CD₃OD): δ 7.43-7.38 (m, 2H), 7.26 (s, 1H), 7.00-6.94 (m,3H), 6.89 (s, 4H), 5.02 (t, 1H, J=7.0 Hz), 4.16-4.09 (q, 2H, J=7.1 Hz),3.14-2.94 (m, 2H), 1.17 (t, 3H, J=7.1 Hz).

(S)-4-[2-(4-(Methoxycarbonyl)thiazol-5-ylamino)-2-(2-phenylthiazole-4-yl)ethyl]phenylsulfamicacid: ¹H NMR (300 MHz, MeOH-d₄) δ 7.97-8.00 (m, 3H), 7.48-7.52 (m, 3H),7.22 (s, 1H), 7.03-7.13 (m, 4H), 4.74 (t, J=6.6 Hz, 1H), 3.88 (s, 3H),3.28-3.42 (m, 2H).

(S)-4-[2-(5-Phenyloxazol-2-ylamino)-2-(2-phenylthiazol-4-yl)ethyl]-phenylsulfamicacid: ¹H NMR (300 MHz, MeOH-d₄) δ 7.94-7.96 (m, 2H), 7.45-7.49 (m, 5H),7.32 (t, J=7.8 Hz, 2H), 7.12 (s, 1H), 7.19 (t, J=7.2 Hz, 1H), 7.12 (s,4H), 7.05 (s, 1H), 5.15 (t, J=6.4 Hz, 1H), 3.34 (dd, J=14.1 and 8.4 Hz,1H), 3.18 (dd, J=14.1 and 8.4 Hz, 1H).

(S)-4-{2-[5-(4-Acetamidophenyl)oxazol-2-ylamino]-2-(2-phenylthiazol-4-yl)ethyl}phenylsulfamicacid: ¹H NMR (300 MHz, MeOH-d₄) δ 7.92-7.94 (m, 2H), 7.55-7.58 (m, 2H),7.39-7.50 (m, 5H), 7.26 (s, 1H), 7.12 (s, 4H), 7.02 (s, 1H0), 5.14 (t,J=7.8 Hz, 1H), 3.13-3.38 (m, 2H), 2.11 (s, 3H).

4-((S)-2-(5-(2,4-Difluorophenyl)oxazole-2-ylamino)-2-(2-phenylthiazole-4-yl)ethyl)phenylsulfamicacid: ¹H NMR (300 MHz, MeOH-d₄) δ 7.97-7.99 (m, 2H), 7.54-7.62 (m, 1H),7.45-7.50 (m, 3H), 7.28 (s, 1H), 7.12 (s, 4H), 6.97-7.06 (m, 3H),5.15-5.20 (m, 1H), 3.28-3.40 (m, 1H), 3.20 (dd, J=13.8 and 8.4 Hz, 1H).

4-{(S)-2-[5-(3-Methoxyphenyl)oxazol-2-ylamino]-2-[(2-thiophen-2-yl)thiazole-4-yl]ethyl}phenylsulfamicacid: ¹H NMR (300 MHz, MeOH-d₄) δ 7.55-7.60 (m, 2H), 7.26 (t, J=8.1 Hz,1H), 7.21 (s, 1H), 7.04-7.15 (m, 8H), 6.77-6.81 (m, 1H), 5.10 (t, J=6.3Hz, 1H), 3.81 (s, 3H), 3.29-3.36 (m, 1H), 3.15 (dd, J=14.1 and 8.4 Hz,1H).

(S)-4-[2-(4,6-Dimethylpyrimidin-2-ylamino)-2-(2-methylthiazole-4-yl)ethyl]phenylsulfamicacid: ¹H NMR (300 MHz, MeOH-d₄) δ 7.00-7.10 (m, 5H), 6.44 (s, 1H), 5.50(t, J=7.2 Hz, 1H), 3.04-3.22 (m, 2H), 2.73 (s, 3H), 2.27 (s, 6H).

(S)-4-[2-(4-Hydroxy-6-methylpyrimidine-2-ylamino)-2-(2-methylthiazole-4-yl)ethyl]phenylsulfamicacid: ¹H NMR (300 MHz, MeOH-d4) δ 7.44 (d, J=8.4 Hz, 2H), 6.97-7.10 (m,4H), 5.61 (s, 1H), 5.40-5.49 (m, 1H), 3.10-3.22 (m, 2H), 2.73 (s, 3H),2.13 (s, 3H).

The first aspect of Category X of the present disclosure relates tocompounds having the formula:

wherein R¹ is heteroaryl and R⁴ is further described herein below inTable XIX.

TABLE XIX No. R⁴ R¹ S788 phenyl 4-(methoxycarbonyl)thiazol-5-yl S789phenyl 4-[(2-methoxy-2-oxoethyl)carbamoyl]thiazol-5-yl S790 phenyl5-[1-N-(2-methoxy-2-oxoethyl)-1-H-indol-3-yl]oxazol-2-yl S791 phenyl5-(2-methoxyphenyl)oxazol-2-yl S792 phenyl5-[(S)-1-(tert-butoxycarbonyl)-2-phenylethyl]oxazol-2-yl S793 phenyl5-[4-(methylcarboxy)phenyl]oxazol-2-yl S794 phenyl5-(3-methoxybenzyl)oxazol-2-yl S795 phenyl 5-(4-phenyl)oxazol-2-yl S796phenyl 5-(2-methoxyphenyl)thiazol-2-yl S797 phenyl5-(3-methoxyphenyl)thiazol-2-yl S798 phenyl5-(4-fluorophenyl)thiazol-2-yl S799 phenyl5-(2,4-difluorophenyl)thiazol-2-yl S800 phenyl5-(3-methoxybenzyl)thiazol-2-yl S801 phenyl4-(3-methoxyphenyl)thiazol-2-yl S802 phenyl4-(4-fluorophenyl)thiazol-2-yl S803 thiophen-2-yl4-(methoxycarbonyl)thiazol-5-yl S804 thiophen-2-yl4-[(2-methoxy-2-oxoethyl)carbamoyl]thiazol-5-yl S805 thiophen-2-yl5-[1-N-(2-methoxy-2-oxoethyl)-1-H-indol-3-yl]oxazol-2-yl S806thiophen-2-yl 5-(2-methoxyphenyl)oxazol-2-yl S807 thiophen-2-yl5-[(S)-1-(tert-butoxycarbonyl)-2-phenylethyl]oxazol-2-yl S808thiophen-2-yl 5-[4-(methylcarboxy)phenyl]oxazol-2-yl S809 thiophen-2-yl5-(3-methoxybenzyl)oxazol-2-yl S810 thiophen-2-yl5-(4-phenyl)oxazol-2-yl S811 thiophen-2-yl5-(2-methoxyphenyl)thiazol-2-yl S812 thiophen-2-yl5-(3-methoxyphenyl)thiazol-2-yl S813 thiophen-2-yl5-(4-fluorophenyl)thiazol-2-yl S814 thiophen-2-yl5-(2,4-difluorophenyl)thiazol-2-yl S815 thiophen-2-yl5-(3-methoxybenzyl)thiazol-2-yl S816 thiophen-2-yl4-(3-methoxyphenyl)thiazol-2-yl S817 thiophen-2-yl4-(4-fluorophenyl)thiazol-2-yl S818 cyclopropyl4-(methoxycarbonyl)thiazol-5-yl S819 cyclopropyl4-[(2-methoxy-2-oxoethyl)carbamoyl]thiazol-5-yl S820 cyclopropyl5-[1-N-(2-methoxy-2-oxoethyl)-1-H-indol-3-yl]oxazol-2-yl S821cyclopropyl 5-(2-methoxyphenyl)oxazol-2-yl S822 cyclopropyl5-[(S)-1-(tert-butoxycarbonyl)-2-phenylethyl]oxazol-2-yl S823cyclopropyl 5-[4-(methylcarboxy)phenyl]oxazol-2-yl S824 cyclopropyl5-(3-methoxybenzyl)oxazol-2-yl S825 cyclopropyl 5-(4-phenyl)oxazol-2-ylS826 cyclopropyl 5-(2-methoxyphenyl)thiazol-2-yl S827 cyclopropyl5-(3-methoxyphenyl)thiazol-2-yl S828 cyclopropyl5-(4-fluorophenyl)thiazol-2-yl S829 cyclopropyl5-(2,4-difluorophenyl)thiazol-2-yl S830 cyclopropyl5-(3-methoxybenzyl)thiazol-2-yl S831 cyclopropyl4-(3-methoxyphenyl)thiazol-2-yl S832 cyclopropyl4-(4-fluorophenyl)thiazol-2-yl

Compounds according to the first aspect of Category X can be prepared bythe procedure outlined in Scheme XXII and described herein below inExample 23.

EXAMPLE 234-((S)-2-(2-(3-Chlorophenyl)acetamido)-2-(2-(thiophen-2-yl)oxazol-4-yl)ethyl)phenylsulfamicacid (64)

Preparation of(S)-2-(4-nitrophenyl)-1-[(thiophen-2-yl)oxazol-4-yl]ethanaminehydrobromide salt (62): A mixture of (S)-tert-butyl4-bromo-1-(4-nitrophenyl)-3-oxobutan-2-ylcarbamate, 7, (38.7 g, 100mmol), and thiophen-2-carboxamide (14 g, 110 mmol) (available from AlfaAesar) in CH₃CN (500 mL) is refluxed for 5 hours. The reaction mixtureis cooled to room temperature and diethyl ether (200 mL) is added to thesolution. The precipitate which forms is collected by filtration. Thesolid is dried under vacuum to afford the desired product which can beused for the next step without purification.

Preparation of2-(3-chlorophenyl)-N-{(S)-2-(4-nitrophenyl)-1-[2-(thiophen-2-yl)oxazol-4-yl]ethyl}acetamide(63): To a solution of(S)-2-(4-nitrophenyl)-1-[(thiophen-2-yl)oxazol-4-yl]ethanamine HBr, 47,(3.15 g, 10 mmol) 3-chlorophenyl-acetic acid (1.70 g, 10 mmol) and1-hydroxybenzotriazole (HOBt) (0.70 g, 5.0 mmol) in DMF (50 mL) at 0°C., is added 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide (EDCI) (1.90g, 10 mmol) followed by triethylamine (4.2 mL, 30 mmol). The mixture isstirred at 0° C. for 30 minutes then at room temperature overnight. Thereaction mixture is diluted with water and extracted with EtOAc. Thecombined organic phase is washed with 1 N aqueous HCl, 5% aqueousNaHCO₃, water and brine, and dried over Na₂SO₄. The solvent is removedin vacuo to afford the desired product which is used without furtherpurification.

Preparation of—((S)-2-(2-(3-chlorophenyl)acetamido)-2-(2-(thiophen-2-yl)oxazol-4-yl)ethyl)phenylsulfamicacid (64):2-(3-chlorophenyl)-N-{(S)-2-(4-nitrophenyl)-1-[2-(thiophen-2-yl)oxazol-4-yl]ethyl}acetamide,63, (3 g) is dissolved in MeOH (4 mL). A catalytic amount of Pd/C (10%w/w) is added and the mixture is stirred under a hydrogen atmosphere 18hours. The reaction mixture is filtered through a bed of CELITE™ and thesolvent is removed under reduced pressure. The crude product isdissolved in pyridine (12 mL) and treated with SO₃-pyridine (0.157 g).The reaction is stirred at room temperature for 5 minutes after which a7% solution of NH₄OH is added. The mixture is then concentrated and theresulting residue can be purified by reverse phase chromatography toafford the desired product as the ammonium salt.

The second aspect of Category X of the present disclosure relates tocompounds having the formula:

wherein R¹ is aryl and R² and R³ are further described herein below inTable XX.

TABLE XX No. R² R³ R¹ T833 methyl hydrogen phenyl T834 methyl hydrogenbenzyl T835 methyl hydrogen 2-fluorophenyl T836 methyl hydrogen3-fluorophenyl T837 methyl hydrogen 4-fluorophenyl T838 methyl hydrogen2-chlorophenyl T839 methyl hydrogen 3-chlorophenyl T840 methyl hydrogen4-chlorophenyl T841 ethyl hydrogen phenyl T842 ethyl hydrogen benzylT843 ethyl hydrogen 2-fluorophenyl T844 ethyl hydrogen 3-fluorophenylT845 ethyl hydrogen 4-fluorophenyl T846 ethyl hydrogen 2-chlorophenylT847 ethyl hydrogen 3-chlorophenyl T848 ethyl hydrogen 4-chlorophenylT849 thien-2-yl hydrogen phenyl T850 thien-2-yl hydrogen benzyl T851thien-2-yl hydrogen 2-fluorophenyl T852 thien-2-yl hydrogen3-fluorophenyl T853 thien-2-yl hydrogen 4-fluorophenyl T854 thien-2-ylhydrogen 2-chlorophenyl T855 thien-2-yl hydrogen 3-chlorophenyl T856thiene-2-yl hydrogen 4-chlorophenyl

Compounds according to the second aspect of Category X can be preparedby the procedure outlined in Scheme XXIII and described herein below inExample 24.

EXAMPLE 24{4-[2-(S)-(4-Ethyloxazol-2-yl)-2-phenylacetylaminoethyl]-phenyl}sulfamicacid (67)

Preparation of (S)-1-(4-ethyloxazol-2-yl)-2-(4-nitrophenyl)ethanamine(65): A mixture of [1-(S)-carbamoyl-2-(4-nitrophenyl)ethyl-carbamic acidtert-butyl ester, 1, (10 g, 32.3 mmol) and 1-bromo-2-butanone (90%, 4.1mL, 36 mmol) in CH₃CN (500 mL) is refluxed for 18 hours. The reactionmixture is cooled to room temperature and diethyl ether is added to thesolution and the precipitate which forms is removed by filtration and isused without further purification.

Preparation ofN-[1-(4-ethyloxazol-2-yl)-2-(4-nitrophenyl)ethyl]-2-phenyl-acetamide(66): To a solution of(S)-1-(4-ethyloxazol-2-yl)-2-(4-nitrophenyl)ethanamine, 65, (2.9 g, 11mmol), phenylacetic acid (1.90 g, 14 mmol) and 1-hydroxybenzotriazole(HOBt) (0.94 g, 7.0 mmol) in DMF (100 mL) at 0° C., is added1-(3-dimethylamino-propyl)-3-ethylcarbodiimide (EDCI) (2.68 g, 14 mmol)followed by triethylamine (6.0 mL, 42 mmol). The mixture is stirred at0° C. for 30 minutes then at room temperature overnight. The reactionmixture is diluted with water and extracted with EtOAc. The combinedorganic phase is washed with 1 N aqueous HCl, 5% aqueous NaHCO₃, waterand brine, and dried over Na₂SO₄. The solvent is removed in vacuo toafford the desired product which is used without further purification.

Preparation of{4-[2-(S)-(4-ethyloxazol-2-yl)-2-phenylacetylaminoethyl]-phenyl}sulfamicacid (67):N-[1-(4-ethyloxazol-2-yl)-2-(4-nitrophenyl)ethyl]-2-phenyl-acetamide,66, (0.260 g) is dissolved in MeOH (4 mL). A catalytic amount of Pd/C(10% w/w) is added and the mixture is stirred under a hydrogenatmosphere 18 hours. The reaction mixture is filtered through a bed ofCELITE™ and the solvent is removed under reduced pressure. The crudeproduct is dissolved in pyridine (12 mL) and treated with SO₃-pyridine(0.177 g, 1.23). The reaction is stirred at room temperature for 5minutes after which a 7% solution of NH₄OH (10 mL) is added. The mixtureis then concentrated and the resulting residue is purified by reversephase chromatography to afford the desired product as the ammonium salt.

Methods

The vascular endothelium lines the inside of all blood vessels, forminga non-thrombogenic surface that controls the entry and exit of plasmaand white blood cells to and from the bloodstream. The quiescentendothelium has turnover rates of months to years, and proliferates onlyfollowing angiogenic activation. The loss of endothelial quiescence is acommon feature of conditions such as inflammation, atherosclerosis,restenosis, angiogenesis and various types of vasculopathies.

Vasculogenesis and angiogenesis are down-regulated in the healthy adultand are, except for the organs of the female reproductive system, almostexclusively associated with pathology when angiogenesis is induced bymicroenvironmental factors such as hypoxia or inflammation. Thesepathological processes associated with, or induced by, angiogenesisinclude diseases as diverse as cancer, psoriasis, macular degeneration,diabetic retinopathy, thrombosis, and inflammatory disorders includingarthritis and athrerosclerosis. However, in certain instancesinsufficient angiogenesis can lead to diseaeses such as ischemic heartdisease and pre-eclampsia.

The quiescent vascular endothelium forms a tight barrier that controlsthe passage of plasma and cells from the bloodstream to the underlyingtissues. Endothellial cells adhere to each other through junctionaltransmembrane proteins that are linked to specific intracelllarstructural and signaling complexes. The endothelial layer can undergo atransition from the resting state to the active state wherein activationof the endothelium results in the expression of adhesion molecules. Thisendothelium activation is a prerequisite for initiating angiogensesis,inflammation and inflammation associated diseases.

Tie-2, a receptor-like tyrosine kinase exclusively expressed inendothelial cells that controls endothelial differentiation. Tie-2 bindsand is activated by the stimulatory ligand angiopoeitin-1 (Ang-1) whichpromotes autophosphorylation of the Tie-2 receptor leading to a cascadeof events that results in stabilization of vascular structures bypromoting endothelial cell viability and preventing basement membranedissolution. As such, Tie-2 activation is a method for attenuatingleaking vasculature by maintaining a quiescent, intact vascularendothelium. Tie-2 activation is inhibited by Ang-2, which exhibitsAng-1 antagonism by competitively binding to Tie-2 and thus blockingphosphorylation of Tie-2. Elevated levels of Ang-2 have been found to beassociated with inflammatory diseases, inter alia, sepsis, lupus,inflammatory bowel disease and metastatic diseases such as cancer.

During periods of high Ang-2 levels, fissures or breaks in theendothelium form which results in vascular leak syndrome. Vascular leaksyndrome results in life-threatening effects such as tissue andpulmonary edema. For many disease states elevated Ang-2 levels are clearmarkers that a disease state or condition exists. Once a disease statehas been resolved, the Ang-1/Ang-2 balance returns and the vascularendothelium is stabilized.

Amplification of Tie-2 Signaling

In conditions wherein the normal balance between Ang-1 and Ang-2 hasbeen disrupted, the disclosed compounds have been found to amplify Tie-2signaling by inhibiting dephosphorylation of phosphorylated Tie-2 viainhibition of Human Protein Tyrosine Phosphatase-β (HPTP-β). Inaddition, the disclosed compounds can be used in varying amounts toincrease the Tie-2 signaling in a very controlled manner, and totherefore titrate the level of Tie-2 amplification.

IL-2 Induced Vascular Leak: Treatment of Metastatic Cancers

Immunotherapy is one method of treating cancer. Up-regulation of thebody's own immune system is one aspect of immunotherapy. Among the manyimmune system signaling molecules is interleukin-2 (IL-2) which isinstrumental in the body's natural response to microbial infection andin discriminating between foreign (non-self) and self High-doseinterleukin-2 (HDIL-2) is an FDA approved treatment for patients withmetastatic renal cell carcinoma (RCC) and metastatic melanoma. Althoughit has been reported that only 23% of those subjects given this therapyshow a tumor response, the duration of this response can exceed 10 years(Elias L. et al., “A literature analysis of prognostic factors forresponse and quality of response of patients with renal cell carcinomato interleukin-2-based therapy.” Oncology (2001); 61: pp. 91-101). Assuch, IL-2 therapy is the only available treatment that offers thepotential for cure.

Gallagher (Gallagher, D. C. et al., “Angiopoietin 2 Is a PotentialMediator of High-Dose Interleukin 2-Induced Vascular Leak” Clin CancerRes (2007):13(7) 2115-2120) reports that elevated levels ofangiopoietin-2 are found in patients treated with high doses of IL-2 andsuggests that overcoming Ang-2 blockade of Tie-2 signaling might becurative for vascular leak syndrome which is a side effect of thistherapy. As many as 65% of patients receiving this IL-2 therapy willnecessarily interrupt or discontinue treatment due to VLS. VLS istypically characterized by 2 or more of the following 3 symptoms(hypotension, edema, hypoalbuminemia), although other manifestationsinclude prerenal azotemia, metabolic acidosis, pleural effusions, andnon-cardiogenic pulmonary edema.

IL-2 is known to cause endothelial cell activation, however, with lossof proper barrier function. Amplification of Tie-2 signaling during HighDose IL-2 immunotherapy would lead to attenuation of vascular leakagesince Tie-2 stimulation promotes endothelial cell stability. As such, byadministering an agent that can amplify Tie-2 signaling, vascularstability can be increased and, hence, the side effects of high IL-2dosing mitigated. The disclosed compounds can amplify Tie-2 signalingunder the conditions of low angiopoietin-1 concentrations or when highconcentrations of angiopoietin-2 are present as in IL-2 treatedpatients.

By amplifying Tie-2 signaling without affecting Ang-2 levels, the use ofelevated levels of Ang-2 as a potential pathology marker is retained.For example, a patient suffering from an inflammatory disease such assepsis will normally have an elevated Ang-2 level that acts to suppressAng-1 stimulation of Tie-2. This elevated Ang-2 results in edema whichis a symptom of vascular leakage. The present methods, by amplifyingTie-2 signaling without affecting the Ang-2 level, provide a method foralleviating the symptoms that are associated with vascular leak whileretaining the ability to use Ang-2 levels as a measure of diseaseprogress and resolution.

Reduction of Vascular Leak Caused by an Anticancer Therapy

The following demonstrates the effectiveness of the disclosed compoundson Tie-2 signal amplification, and thus, the alleviation of vascularleakage due to administration of high doses of an anticancer treatmentthat induces vascular leak syndrome, i.e., IL-2.

Twenty-five mice were used for the following experiment. Five areselected as the control and received no treatment. The remaining twentymice were divided into four groups of five mice each and dosed asfollows over a period of 5 days:

Low dose of IL-2 was at 180,000 units per day

High dose of IL-2 was at 400,000 units per day

Tie-2 signal amplifier at 40 mg/kg for the first 2 days, then at 20mg/kg for 3 days.

The animals were monitored for symptoms related to vascular leaksyndrome seen in patients treated with high doses of IL-2, inter alia,blood pressure (hyportension/shock), viability (death), lung histology(VSL pathology) and serum cytokine etc. (VSL mechanistic analysis.

The disclosed compound,4-{(S)-2-[(S)-2-(methoxycarbonylamino)-3-phenylpropanamido]-2-[2-(thiophen-2-yl)thiazol-4-yl]ethyl}phenylsulfamicacid, D91, having the formula:

was used as the Tie-2 signal amplifier. As depicted in FIG. 1 the bloodpressure of the animals treated with a high dose of IL-2 went to 0 mm Hg(death), whereas the animals treated with4-{(S)-2-[(S)-2-(methoxycarbonylamino)-3-phenyl-propanamido]-2-[(2-(thiophen-2-yl)thiazol-4-yl]ethyl}phenylsulfamicacid ammonium salt showed little effect on blood pressure even in thecase of those animals treated with the high dose of IL-2.

As depicted in FIG. 2, of the animals receiving high doses of IL-2, 60%showed clinical symptoms of shock, whereas the animals receiving highdoses of IL-2 and the Tie-2 signal amplifier4-{(S)-2-[(S)-2-(methoxycarbonylamino)-3-phenyl-propanamido]-2-[2-(thiophen-2-yl)thiazol-4-yl]ethyl}phenylsulfamicacid ammonium salt showed no signs of shock.

As depicted in FIG. 3, of the animals receiving high doses of IL-2, 40%died, whereas the animals receiving high doses of IL-2 and the Tie-2signal amplifier4-{(S)-2-[(S)-2-(methoxycarbonylamino)-3-phenyl-propanamido]-2-[2-(thiophen-2-yl)thiazol-4-yl]ethyl}phenylsulfamicacid ammonium salt survived.

FIG. 4 depicts a summary of the status of the animals treated with highdoses of IL-2, those treated with high doses of IL-2 and the Tie-2signal amplifier4-{(S)-2-[(S)-2-(methoxy-carbonylamino)-3-phenyl-propanamido]-2-[2-(thiophen-2-yl)thiazol-4-yl]ethyl}phenylsulfamicacid ammonium salt versus control.

The disclosed compounds can act as Tie-2 signaling amplifiers and,therefore can be used as an effective therapy to reduce vascular leak.The disclosed compounds can be co-administered with IL-2 or administeredseparately. As such, the IL-2 and Tie-2 signal amplifier can beadministered in any order and by any method, for example, intravenously,orally, by patch, subcutaneous injection, and the like.

Disclosed herein is a method for treating renal cell carcinoma byadministering to a patient in need of treatment a therapy thatcomprises:

-   -   a) an effective amount of interleukin-2 such that an immune        response is provided; and    -   b) an effective amount of one or more of the disclosed        compounds;    -   wherein the interleukin-2 and the disclosed compounds can be        administered together or in any order.

As such, disclosed herein is a method for treating renal cell carcinomaby contacting a patient with a composition comprising:

-   -   a) a high dose of interleukin-2; and    -   b) an effective amount of one or more of the compounds disclosed        herein.

Disclosed herein is a method for treating metastatic melanoma bycontacting a patient with a composition comprising:

-   -   a) a high dose of interleukin-2; and    -   b) an effective amount of one or more of the compounds disclosed        herein.

Further disclosed is a method for treating metastatic melanoma bycontacting a patient with a series of compositions, wherein thecompositions can be administered in any order and at any effectiveamount, a first composition comprising, a high dose of interleukin-2 andthe second composition comprising an effective amount of one or more ofthe disclosed compounds.

Still further disclosed is a method for treating renal cell carcinoma bycontacting a patient with a series of compositions, wherein thecompositions can be administered in any order and at any effectiveamount, a first composition comprising a high dose of interleukin-2 andthe second composition comprising an effective amount of one or more ofthe disclosed compounds.

Disclosed herein is a method for treating metastatic melanoma byadministering to a patient in need of treatment a therapy thatcomprises:

-   -   a) an effective amount of interleukin-2 such that an immune        response is provided; and    -   b) an effective amount of one or more of the disclosed        compounds;    -   wherein the interleukin-2 and the one or more disclosed        compounds can be administered together or in any order.

Also disclosed herein is a method for treating metastatic melanoma byadministering to a patient in need of treatment a therapy thatcomprises:

-   -   a) an effective amount of interleukin-2 such that an immune        response is provided; and    -   b) an effective amount of one or more of the disclosed        compounds;    -   wherein the interleukin-2 and the one or more disclosed        compounds can be administered together or in any order.

Tumor growth is often a multi-step process that starts with the loss ofcontrol of cell proliferation. The cancerous cell then begins to dividerapidly, resulting in a microscopically small, spheroid tumor: an insitu carcinoma. As the tumor mass grows, the cells will find themselvesfurther and further away from the nearest capillary. Finally the tumorstops growing and reaches a steady state, in which the number ofproliferating cells counterbalances the number of dying cells. Therestriction in size is caused by the lack of nutrients and oxygen. Intissues, the oxygen diffusion limit corresponds to a distance of 100 μmbetween the capillary and the cells, which is in the range of 3-5 linesof cells around a single vessel. In situ carcinomas may remain dormantand undetected for many years and metastases are rarely associated withthese small (2 to 3 mm²), avascular tumors.

When a tumor's growth is stopped due to a lack of nutrients and/oroxygen, this reduction in tumor vasculature also limits the ability ofanti-tumor drugs to be delivered to the malignant cells. Moreover, ifthere is a slight increase in tumor vasculature, this will allowdelivery of anti-tumor therapies to the malignant cells withoutinitiating metastasis. As such, the disclosed compounds when used toslightly amplify Tie-2 signaling can be used to increase blood flow tothe tumor cells without setting off metastasis or uncontrolled tumorcell proliferation while providing a method for delivering anti-cancerdrugs to malignant cells.

Disclosed herein is a method for treating cancer comprising,administering to a patient in need an amount of one or more of thedisclosed compounds that amplify Tie-2 signaling in conjunction with achemotherapeutic compound or immunotherapeutic compound. By“chemotherapeutic compound” is meant any composition which comprises oneor more compounds that can be administered to a patient for the purposesof attenuating or eliminating the presence of tumor cells. By “slightlyamplify Tie-2 signaling” is meant that a sufficient amount of adisclosed compound is administered to a patient such that the amount oftumor cell vasculature is increased such that the increased circulationallows for delivery of the anti-tumor compound or therapy withoutinstigating tumor growth wherein the rate of tumor cell growth is lessthan the rate of tumor cell death.

Disclosed herein is a method for treating a cancer wherein the cancer ismedulloblastoma, ependymoma, ogliodendroglioma, pilocytic asrocytoma,diffuse astrocytoma, anaplasic astrocytoma, or glioblastoma. Furtherdisclosed is a method for treating a tumor or invasive cancer chosenfrom medulloblastoma, ependymoma, ogliodendroglioma, pilocyticasrocytoma, diffuse astrocytoma, anaplasic astrocytoma, or glioblastomawherein an effective amount of one or more disclosed Tie-2 signalamplifiers is administered to a subject. In addition, the method cancomprise monitoring the Ang-2 level of the subject while the subject isundergoing treatment.

Angiopoietin-2 is significantly correlated to Gleason Score, metastases,and to cancer specific survival (Lind A. J. et al., “Angiopoietin-2expression is related to histological grade, vascular density,metastases, and outcome in prostate cancer” Prostate (2005) 62:394-299).Angiopoietin-2 was found to be expressed in prostate cancer bone, liverand lymph node metastases, but with little to no angiopoietin-1expression in prostate cancer tumor cells in bone, liver, and lymphnodes (Morrissey C. et al. “Differential expression of angiogenesisassociated genes in prostate cancer bone, live and lymph nodemetastases” Clin. Exp Metastasis (2008) 25:377-388). As such, monitoringthe level of Ang-2 provides a method for evaluating the presence ofprostate cancer and the spread of prostate cancer cells throughout thebody due to vascular leakage.

Vasculature Stabilization in Diseases Caused by Pathogens

Disclosed herein is a method for treating vascular leak syndrome causedby one or more pathogens, comprising administering to a human or othermammal in need of treatment an effective amount of one or more of thedisclosed compounds.

Also disclosed herein is a method for treating vascular leak syndromecaused by one or more pathogens, comprising administering to a human orother mammal in need of treatment a composition comprising:

-   -   a) an effective amount of one or more compounds effective        against a pathogen present in the human or mammal; and    -   b) an effective amount of one or more of the disclosed        compounds;    -   wherein the of one or more compounds effective against a        pathogen and the one or more of the disclosed compounds can be        administered together or in any order.

Further disclosed herein is a method for preventing vascular leaksyndrome in a human or other mammal diagnosed with an pathogen that canproduce vascular leak syndrome in a human or mammal, comprisingadministering to a human or mammal a composition comprising:

-   -   a) an effective amount of one or more compounds effective        against a pathogen present in the human or mammal; and    -   b) an effective amount of one or more of the disclosed        compounds;        wherein the of one or more compounds effective against a        pathogen and the one or more of the disclosed compounds can be        administered together or in any order.

Increased amplification of Tie-2 signaling using the disclosed compoundsprovides a method for stabilizing vasculature without the need to affectAng-1 and/or Ang-2 levels. Disclosed herein are methods for stabilizingvasculature, comprising administering to a patient in need an effectiveamount of one or more of the disclosed Tie-2 amplifiers.

Because the disclosed compounds can amplify Tie-2 signaling withoutincreasing the amount of Ang-2, monitoring the amount of Ang-2 in bloodserum of a subject while administering to a subject one or more of thedisclosed compounds, serves as a method for determining the course ofvarious illnesses or disease states associated with vascular leaksyndrome, for example, sepsis as a result of infection. As such,disclosed is a method for stabilizing vasculature in a patient sufferingfrom an inflammatory disease wherein the level of angiopoietin-2 iselevated, comprising:

-   -   a) administering to a subject an effective amount of one or more        of the disclosed compounds as a treatment;    -   b) monitoring the level of angiopoietin-2 present in the        subject; and    -   c) discontinuing treatment when the angiopoietin-2 level returns        to a normal range.

What is meant herein by “normal angiopoietin-2 level” is an amount ofAng-2 in blood serum of from about 1 ng/mL to about 2 ng/mL.Alternatively, the level of Ang-2 can be determined for an individualsuffering from a disease state, for example, severe sepsis and the levelof Ang-2 can be monitored until the amount of Ang-2 in the subject'sserum drop to a level that is nearer the normal range. In this case, theco-administration of a drug can be continued or discontinued. Therefore,disclosed herein is a method for stabilizing the vasculature of asubject during a course of treatment, comprising:

-   -   a) co-administering to a subject an effective amount of one or        more of the disclosed compounds and one or more drugs as a        treatment;    -   b) monitoring the level of angiopoietin-2 present in the        subject; and    -   c) discontinuing the administration of the one or more drugs and        selecting one or more other drugs for use as a treatment if the        level of serum angiopoetin-2 does not decrease.

The disclosed compounds, while stabilizing the vasculature of a patientsuch that a course of treatment against a pathogen can be sustained, canalso be used to stabilize a subject during a period wherein an effectivetreatment against a pathogen is being determined That is, the disclosedcompounds by themselves can have a beneficial effect on the outcome ofdiseases caused by pathogens by reducing vascular leak and itscomplications.

Liposaccharide Induced Vascular Leak Model

The following liposaccharide induced vascular leakage model can be usedto confirm the ability of the disclosed compounds to decrease theeffects of vascular leak syndrome caused by pathogens. In the followingexample acute kidney injury (AKI) was studied to show the effect of D91as a successful strategy that can preserve renal endothelial Tie2phosphorylation in septic AKI.

Acute kidney injury is a frequent and serious problem in hospitalizedpatients, and is frequently a consequence of sepsis. The renalendothelium plays a key role in sepsis induced AKI. Activated Tie2,expressed mainly in endothelial cell surfaces, has many effects whichare expected to be protective in sepsis-induced AKI, such asdownregulation of adhesion molecule expression, inhibition of apoptosis,preservation of barrier function, and angiogenesis.

Male C57BL6 mice, 9 to 10 weeks old, were injected i.p. with 0.2 mg E.Coli lipopolysaccharide per 25 g body weight at time 0. Mice wereinjected with D91 at 50 mg/kg, 50 μL versus vehicle (50 μL) at the time0, 8, and 16 hours. Mice were sacrifiecd at 24 hours after LPSinjection. Vehicle control (saline) injected mice were studied inparallel as controls. Serum samples were analyzed for blood ureanitrogen (BUN) as a marker of kidney function.

As shown in FIG. 7, the level of blood urine nitrogen (BUN) in theanimals receiving only LPS (◯) was approximately 150 mg/dL at 24 hours,whereas animals treated with 50 mg/kg of D91(●) had a blood urinenitrogen level of less than 80 mg/dL. These data show that D91 iscapable of protecting mice against AKI in this model.

Tissue samples from the animals were analyzed by high powered fieldmicroscopy to determine the number of polymorphonuclear leukocytespresent. As shown in FIG. 8, the number of PMN cells present in theLPS/vehicle animals was on average 26 whereas the number of PMN cellspresent in animals receiving D91 was on average 12. As such, this modeldemonstrates the effectiveness of D91 in preventing acute kidney injurydue to pathogens, i.e., E. coli.

Phosphatase inhibition by the disclosed PTP-β inhibitors reducesLPS-induced renal vascular leak. Mice were injected with LPS at time 0and D91 or vehicle at 1, 6, and 16 h. Two minutes prior to sacrifice at24 hours 70 kDa fluorescent fixable dextrans were administered byintravenous catheter. Frozen sections showed extrusion of dye beyond thesmall peritubular capillaries was induced by LPS, but is reduced by D91.FIG. 10 a is a micrograph of the control sample for the 70 kDa samplewherein the Letter “G” represents glomerular capillaries where the dyeshould normally be contained. FIG. 10 b represents a renal section takenfrom an LPS treated animal and FIG. 10 c represents a renal sectiontaken from an animal treated with LPS and D91.

The following are non-limiting examples of virsus, bacteria, and otherpathogens where virulence can be controlled by mitigating the degree ofvascular leak that is induced by the organism. The following describetests and assays that can be used to determine the effectiveness of thedisclosed compounds, either alone, or a combination therapy.

Anthrax

Anthrax, the disease caused by Bacillus anthracis, was once a diseasecommonly spread among animals, but there is now a concern that thisdisease will be used as a part of bioterrorism. Inhalation anthrax is adeadly disease for which there is currently no effective treatment.Anthrax toxin, a major virulence factor of this organism, consists ofthree polypeptides: protective antigen (PA), lethal factor (LF), andedema factor (EF). PA is required for binding and translocation of EFand LF into target cells (Collier R. J. et al., (2003) Anthrax toxin.Annu. Rev. Cell Dev. Biol. 19:45-70). As such, lethal factormetalloproteinase is an integral component of the tripartite anthraxlethal toxin that is essential for the onset and progression of anthrax.The injection of lethal toxin (LT is LF plus PA) into animals issufficient to induce some symptoms of anthrax infection, includingpleural effusions indicative of vascular leak and lethality (Beall F. A.et al. (1966) The pathogenesis of the lethal effect of anthrax toxin inthe rat. J. Infect. Dis. 116:377-389; Beall F. A. et al., (1962) Rapidlethal effect in rats of a third component found upon fractionating thetoxin of Bacillus anthracis. J. Bacteriol. 83:1274-1280; Cui X. et al.,(2004) Lethality during continuous anthrax lethal toxin infusion isassociated with circulatory shock but not inflammatory cytokine ornitric oxide release in rats. Am. J. Physiol. Regul. Integr. Comp.Physiol. 286:R699-R709; Fish D. C. et al., (1968) Pathophysiologicalchanges in the rat associated with anthrax toxin. J. Infect. Dis.118:114-124; Klein F. et al., (1962) Anthrax toxin: causative agent inthe death of rhesus monkeys. Science 138:1331-1333; Klein, F. et al.,(1966) Pathophysiology of anthrax. J. Infect. Dis. 116:123-138; andMoayeri M. et al., (2003) Bacillus anthracis lethal toxin inducesTNF-α-independent hypoxia-mediated toxicity in mice. J. Clin. Investig.112:670-682). Early studies of anthrax suggested that lethal toxin killsanimals by inducing nonspecific shock-like manifestations, and recentstudies with mice and rats have confirmed an LT-mediatedcytokine-independent vascular collapse. It has been reported that humansand primates exposed to spores via aerosol, present pleural effusions asthe most common symptom of disease. Histopathological analyses of humansubjects with inhalational anthrax infections display hemorrhaging invarious organs resulting from destruction of both large and smallvessels. Clearly, LT is an important virulence factor and contributes tosome but not all the pathology observed with spore infection.

Recently, LT-mediated endothelial cell killing has been proposed tocontribute to the vascular pathology observed during the course ofanthrax (Kirby, J. E. (2004) Anthrax lethal toxin induces humanendothelial cell apoptosis. Infect. Immun. 72:430-439). Since thisLT-induced endothelial cytotoxicity occurs gradually (over 72 hours) anddeath from LT-mediated vascular collapse can occur in as little as 45min (Ezzell J. W. et al., (1984) Immunoelectrophoretic analysis,toxicity, and kinetics of in vitro production of the protective antigenand lethal factor components of Bacillus anthracis toxin. Infect. Immun.45:761-767), there is a need for a method for preventing increasedvascular leakage due to anthrax lethal toxin.

In Vivo Vascular Leak

The Miles assay (Miles, A. A., and E. M. Miles (1952) Vascular reactionsto histamine, histamine-liberator and leukotaxine in the skin ofguinea-pigs. J. Physiol. 118:228-257 incorporated herein by reference inits entirety) can be used to directly investigate and quantify lethaltoxin, as well as edema toxin (ET [PA plus EF])-mediated vascularleakage in the mouse model. The following is a modified Miles assay asdescribed by Gozes Y. et al., Anthrax Lethal Toxin InducesKetotifen-Sensitive Intradermal Vascular Leakage in Certain Inbred MiceInfect Immun. 2006 February; 74(2): 1266-1272 incorporated herein byreference in its entirety, that can be used to evaluate the disclosedcompounds for their ability to prevent vascular leakage in humans andanimals exposed to anthrax.

Highly pure PA, LF, and mutant LF E687C are purified as previouslydescribed (Varughese M. et al., (1998) Internalization of a Bacillusanthracis protective antigen-c-Myc fusion protein mediated by cellsurface anti-c-Myc antibodies. Mol. Med. 4:87-95 included herein byreference in its entirety). Doses of ET or LT refer to the amount ofeach component (i.e., 100 μg LT is 100 μg PA plus 100 μg of LF). Alldrugs except for azelastine can be purchased from Sigma Aldrich (St.Louis, Mo.); azelastine can be purchased from LKT Laboratories (St.Paul, Minn.).

Animals.

BALB/cJ, DBA/2J, C3H/HeJ, C3H/HeOuJ, WBB6F1/J-Kit^(W)/Kit^(W-v), andcolony-matched wild-type homozygous control mice can be purchased fromThe Jackson Laboratory (Bar Harbor, Me.). BALB/c nude, C57BL/6J nude,and C3H hairless (C3.Cg/TifBomTac-hr) mice can be purchased from TaconicFarms (Germantown, N.Y.). C3H nude mice can be purchased from TheNational Cancer Institute Animal Production Area (Frederick, Md.). Miceare used when they are 8 to 12 weeks old. Except for C3H hairless andnude animals, all mice are shaved 24 hours prior to intradermal (i.d.)injections. In order to assess the susceptibility to systemic LT, miceare injected intraperitoneally (i.p.) with 100 μg LT and observed over 5days for signs of malaise or death. Fischer 344 rats can be purchasedfrom Taconic Farms (Germantown, N.Y.) and used at weights of 150 to 180g. Rats are injected intravenously (i.v.) in the tail vein with 12 μgLT, with or without 250 μg of the mast cell stabilizer drug ketotifenand monitored for the exact time to death.

Miles Assay.

The Miles assay uses i.v. injection of Evans blue dye (which binds toendogenous serum albumin) as a tracer to assay macromolecular leakagefrom peripheral vessels after i.d. injection of test substances. Nudemice and normal shaved mice are injected i.v. with 200 μl of 0.1% Evansblue dye (Sigma Chemical Co., St. Louis, Mo.). After 10 min, 30 μl oftest toxin or control samples (PA only, LF only, EF only, orphosphate-buffered saline) are injected i.d. in both left and rightflanks, as well as at single or dual dorsal sites. To quantify theextents of leakage, equally sized (1.0- to 1.5-cm diameter) skin regionssurrounding i.d. injection sites are removed 60 min after injection andplaced in formamide (1 ml) at 41° C. for 48 h, allowing for dyeextraction. The A₆₂₀ of samples is read, and the extent of leakage iscalculated by comparison with phosphate-buffered saline-, PA-, orLF-treated controls.

In experiments wherein the effectiveness of the disclosed compounds aretested for LT-mediated leakage, mice are injected i.v. with Evans blueas described above, and the test compound introduced systemicallythrough i.p. injection 10 min after dye injection. LT was introduced byi.d. injection 30 min after the injection of Evans blue. In anotherembodiment, the compound to be tested can be introduced locally by i.d.injection and LT injected in the same site after 10 min.

Cytotoxicity eExperiments.

MC/9 mast cells can be obtained from ATCC (Manassas, Va.) and grown inDulbecco's modified Eagle's medium supplemented with 1-glutamine (2 mM),2-mercaptoethanol (0.05 mM), Rat T-STIM (BD Biosciences-DiscoveryLabware, Bedford, Mass.) (10%), and fetal bovine serum (FBS, 10% finalconcentration; Invitrogen-GIBCO BRL, Gaithersburg, Md.). Cells are thenseeded at a density of 10⁴/well in 96-well plates prior to treatmentwith various LT concentrations or PA-only controls. After 6, 12, and 24hours, viability is assessed using Promega's CellTiter 96 AQ_(ueous) OneSolution cell proliferation assay (Promega, Madison, Wis.) per themanufacturer's protocol. Alternatively, toxicity assays can be performedin medium provided with all supplements except FBS (serum-free medium).In other embodiments, pooled human umbilical vein endothelial cells(HUVECs) at third to fifth passage can be obtained from Cambrex Corp.(Cambrex, Walkersville, Md.) and grown in an EGM-MV Bulletkit (Cambrex,Walkersville, Md.) in flasks pretreated with endothelial cell attachmentfactor (Sigma, St. Louis, Mo.). For cytotoxicity experiments, cells aretypically seeded in 96-well plates in an EGM-MV Bulletkit. On the day ofassays, this medium is then replaced with M199 medium (Sigma, St. Louis,Mo.) supplemented with 10% FBS or human serum (Sigma, St. Louis, Mo.),and cells are reseeded in 96-well plates at a density of 2×10³/0.1ml/well and treated with various concentrations of LT in triplicate.Cell viability is typically assessed as for MC/9 cells at 24, 48, and 72hour time points.

HUVEC Permeability Assay

HUVEC monolayers can be effectively cultured on Transwell-Clear cellculture inserts (6.5-mm diameter, 0.4-μm pore size; Corning-Costar,Acton, Mass.) in 24-well plates, creating a two-chamber culturing systemconsisting of a luminal compartment (inside the insert) and a subluminalcompartment (the tissue culture plate well). Prior to seeding cells, theinserts are coated with endothelial cell attachment factor (Sigma, St.Louis, Mo.). Prewarmed CS—C medium (Sigma, St. Louis, Mo.) containing10% iron-supplemented calf serum and 1% endothelial cell growth factor(Sigma, St. Louis, Mo.) is added to wells prior to insert placement. AHUVEC cell suspension (200 μL of 5×10⁵ cells/ml) is then added to eachinsert. Cells are cultured at 37° C. in 5% CO₂ for up to 21 days toensure proper formation of a monolayer. For testing barrier function,medium can be changed to RPMI supplemented with 10% FBS or to RPMIwithout serum. To assess barrier function, horseradish peroxidase enzyme(Sigma, St. Louis, Mo.) is added to the inserts (10 mg/well). LT (1μg/mL) or control treatments of PA alone (1 μg/mL) or LF alone (1 μg/mL)are added to duplicate wells, and every hour (for 12 hours), a sample of10 μL was taken from the subluminal compartment and tested for theenzymatic activity of horseradish peroxidase by adding 100 μL substrate[2′,2′-azino-bis(3-ethylbenzthizolin 6-sulfonic acid)] (A-3219; Sigma,St. Louis, Mo.) and reading at 405 nm.

Anthrax Combination Therapy

Increased stabilization of vascular tissue can increase theeffectiveness of known antimicrobials against anthrax infection. Assuch, the disclosed compounds can be evaluated as a combination therapyfor the treatment of anthrax. The following describes a series of assaysthat can be used to determine the effectiveness of the disclosedcompounds as one part of a combination therapy useful for treatinganthrax infections.

LF has been found to cleave mitogen-activated protein kinase kinases(MAPKK), disrupts signal transduction, and leads to macrophage lysis. Assuch, in addition to the Miles Assay, the following cell-based andpeptide cleavage assay can be used to confirm the potency of thedisclosed compounds to inhibit the effect of LT activity. For thefollowing assay, MAPKKide can be purchased from List BiologicalLaboratories (Campbell, Calif. Fluorinated peptide substrate isavailable from Anaspec (San Jose, Calif.).

In Vivo Assays

One week before beginning an evaluation of a combination course oftreatment for anthrax, test compounds (200 mg each) are dissolved in 800μL of DMSO and stored at −20° C. Immediately before injection, eachcompound is diluted in PBS, resulting in a final concentration of 0.5mg/mL in 2% DMSO. Test animal are challenged on day 0 with 2×10⁷ sporesper mouse in PBS through i.p. injection. Treatment was started 24 hoursafter challenge. One example of a suitable treatment regiment is thecombination of ciprofloxacin (50 mg/kg) and one or more of the disclosedcompounds (5 mg/kg). A control sample of untreated animals,ciprofloxacin alone, a disclosed compound alone, and ciprofloxacin incombination with a disclosed compound are given to the animals and theyare monitored twice per day until day 14 after injection.

Ciprofloxacin and the compound to be tested can be convenientlyadministered through parenteral injection with a volume of 200 μL foreach once per day for 10 days. All surviving animals are sacrificed onday 14. Sick animals that appear moribund (i.e., exhibiting a severelyreduced or absent activity or locomotion level, an unresponsiveness toexternal stimuli, or an inability to obtain readily available food orwater, along with any of the following accompanying signs: ruffledhaircoat, hunched posture, inability to maintain normal bodytemperature, signs of hypothermia, respiratory distress, or otherseverely debilitating condition) should be sacrifice on the same daythese symptoms are manifested.

Modulation of Bacterium-Induced Vascular Leak

Pathogenic bacteria are known to cause vascular leak. This inducedvascular leakage inhibits the ability of antimicrobials and otherpharmaceuticals from targeting the invading microorganism. As such, thedisclosed compounds can be used alone or in combination with otherpharmaceutical ingredients to boost the host immune system by preventingexcess vascular leakage that occurs as a result of a bacterialinfection.

Staphylococcus aureus is a major pathogen of gram-positive septic shockand is associated with consumption of plasma kininogen. The effect ofthe disclosed compounds on S. aureus induced vascular leakage activitycan be determined by measuring the activity of these compounds withrespect to two cysteine proteinases that are secreted by S. aureus.Proteolytically active staphopain A (ScpA) induces vascular leakage in abradykinin (BK) B₂-receptor-dependent manner in guinea pig skin. Thiseffect is augmented by staphopain B (SspB), which, by itself, had novascular leakage activity. ScpA also produces vascular leakage activityfrom human plasma.

An important pathophysiologic mechanism of septic shock is hypovolemichypotension that is caused by plasma leakage into the extravascularspace. It has been found that ScpA induced vascular leakage at aconcentration as low as 20 nM within 5 minute after injection into theguinea pig skin—with the reaction being augmented by coexisting SspBindicating that vascular leakage induction by these proteinases occursefficiently in vivo (Imamura T. et al., Induction of vascular leakagethrough release of bradykinin and a novel kinin by cysteine proteinasesfrom Staphylococcus aureus (2005) J. Experimental Medicine 201:10,1669-1676).

Staphopains also can act on LK—whose plasma molar concentration has beenfound to be threefold greater than HK—they also have more opportunity tointeract with substrate than proteinases that generate BK only from HK.Taken together, these results indicate that vascular leakage inductionby staphopains is a mechanism of septic shock induction in severe S.aureus infection that provides an assay for determining theeffectiveness of compounds to modulate vascular leakage.

Vascular Leakage Assay.

Animals can be evaluated for vascular leakage using the followingprocedure. 100 μL of a 1% solution of Evans blue dye (Sigma Aldrich) insaline is injected into the tail vein. Thirty minutes later, mice aresacrificed and perfused with saline via the right ventricle to removeintravascular Evans blue. Lungs are excised and extracted in 1 mL offormamide at 55° C. overnight. Evans blue content is determined as OD₆₂₀minus OD₅₀₀ of the formamide extract.

Influenza

During the years following World War I, it is estimated that more that50 million people were killed by a world-wide influenza pandemic.Recently, the spread of highly pathogenic avian influenza A (H5N1)viruses from Asia also poses a threat of becoming another influenzapandemic. It is thought that highly pathogenic (HP) influenza strainsstimulate a stronger immune response than seasonal strains, causingsevere vascular leakage and lung edema, and eventual death. A study ofmouse immune cell responses following exposure to mouse-adaptedinfluenza viruses that mimic either a seasonal flu or a HP flu strain(Aldridge J. R. et al., (2009). TNF/iNOS-producing dendritic cells arethe necessary evil of lethal influenza virus infection. Proc Natl AcadSci USA 106: 5306-5311).

The compounds disclosed herein can be used as a single pharmaceuticaltherapy to prevent the severity of influenza by mediating the effects ofvascular leak caused by viruses, and, hence, allowing the body's ownimmune system to affect greater resistance to these pathogens. Thefollowing assays can be used to determine the effect of the disclosedcompounds to inhibit viral severity because of improved vascularintegrity.

The disclosed assays can utilize inhibition of viral plaques, viralcytopathic effect (CPE), and viral hemagglutitin.

Proteolytic Sensitivity Assay

The disclosed compounds can be determined to bind to hemagglutinin andthereby destabilize the protein assembly. The following procedure can beused to determine the increase in destabilization and therefore theincreased sensitivity of hemagglutinin to proteolytic attack caused bythe disclosed compounds. At the fusion conformation, HA becomes moresensitive to protease digestion. This property can be used to verify ifa fusion inhibitor interacts with HA (Luo G. et al. “Molecular mechanismunderlying the action of a novel fusion inhibitor of influenza A virus.”J Virol (1997); 71(5):4062-70). Thus, the disclosed compounds, due tothe control of vascular leakage, can be evaluated for their ability toindirectly effect HA digestion by enhancing the body's immune response.

The purified trimer of hemagglutinin ectodomain is incubated with thecompound to be tested at a concentration of 5 μM. The trimers aresubjected to trypsin digestion at pH 7.0 and pH 5.0 with controls ofuntreated HA and HA treated with DMSO which is the solvent used todissolve the test compound. For the pH 5.0 sample, the HA trimers aretreated with a pH 5.0 buffer for 15 minutes and neutralized to pH 7.0.Trypsin (20 ng) is added to the sample in 10 μL and the digestionallowed to proceed for 1 hour at 37° C., The amount of HA present isassessed by a western blot gel electrophoresis using anti-HA (H3)antisera. Samples containing effective inhibitors will provide anincrease in digestion of HA by trypsin.

In addition, combination therapies can provide a method for treatinginfluenza by providing an antiviral medication together with a compoundthat prevents the severity of vascular leakage due to influenza viruses.

An antiviral compound, for example, oseltamivir, can be used for an invivo evaluation of the disclosed combination therapy and to evaluate theeffectiveness of the disclosed compounds. The drug combination isadministered in a single dose to mice infected with the influenzaA/NWS/(H1N1) virus. In some instances, infection of the animals willinclude multiple passage of the virus through their lungs. Oneconvenient protocol involves administering 20 mg/kg per day twice dailyfor 5 days beginning 4 hours prior to virus exposure. The animals arethen challenged with different concentrations of virus, ranging 10-foldfrom 10⁻² (10^(5.75) cell culture 50% infectious doses (CCID₅₀) per mL).Four mice in each group are sacrificed on day 6 and their lungs removed,assigned a consolidation score ranging from 0 (normal) to 4 (maximalplum coloration), weighted, homogenized, the homogenates centrifuged at2000×g for 10 minutes, and varying 10-fold dilutions of the supernataassayed for virus titer in MDCK cells using CPE produced after a 96-hourincubation at 37° C. as endpoint.

The serum taken from mice on day 6 is assayed for a₁-AG using singleradial immunodiffusion kites. Eight additional mice in each group arecontinually observed daily for death for 21 days, and their arterialoxygen saturation (SaO₂) values determined by pulse oximetery (SidwellR. et al., (1992) Utilization of pulse oximetry for the study of theinhibitory effects of antiviral agents on influenza virus in mice.Antimicrob. Agents Chemother. 36, 473-476) on day 3, when SaO₂ declineusually begins to occur, through day 11, when the values are seen todecline to the maximum degree of the animals otherwise die.

Vasogenic Edema

30 adult male Sprague-Dawley rats purchased from Charles River, Germanyand weighing 250-330 g were used for the experiment. Animals were housedat a standard temperature (22±1° C.) and in a light-controlledenvironment (lights on from 7 am to 8 pm) with ad libitum access to foodand water.

Animals were grouped as follows:

-   Group A: 15 rats treated with Vehicle (2 mL/kg, t.i.d., s.c.)    starting 1 hour after stroke onset-   Group B: 15 rats treated with AKB-9778-AS (15 mg/kg, t.i.d., s.c.)    starting 1 hour after stroke onset    tMCAO

Transient focal cerebral ischemia was produced by MCA occlusion in maleSprague-Dawley rats according to Koizumi with modifications (Koizumi etal., Jpn. J. Stroke 8:1-8, 1986). The rats were anesthetized withisoflurane in 70% N₂O and 30% O₂; flow 300 mL/min. 2-3 min anesthesiainduction with 5% isoflurane after which 1-2% isoflurane. The rectaltemperature was maintained above 36.0° C. with a homeothermic blanketsystem. After a midline skin incision, the right common carotid artery(CCA) was exposed, and the external carotid artery (ECA) was ligateddistal from the carotid bifurcation. A 0.25-mm diameter monofilamentnylon thread, with tip blunted, was inserted 22-23 mm into the internalcarotid artery (ICA) up to the origin of MCA. The wound was temporarilyclosed and the rats were allowed to recover. After 60 min of ischemia,the rats were re-anesthetized and MCA blood flow was restored by removalof the thread. The wounds were closed, disinfected, and the animals wereallowed to recover from anesthesia. The rats were carefully monitoredfor possible post-surgical complications after the tMCAO. The rats werefed with standard laboratory diet suspended in tap water.

D91 or vehicle was administered s.c. three times a day. Treatment wasgiven 1, 8, 16, 23, 32, 40 and 47 h after the onset of occlusion.Administration volume was 2 ml/kg and the vehicle is sterile saline. Thebody weight of each animal is measured daily. MRI at 24 and 48 hours:Absolute T2 and Spin Density for Vasogenic Edema and Infarct Volume

T2-MRI was performed at 24 and 48 hours post-ischemia in a horizontal 7Tmagnet with bore size 160 mm (Magnex Scientific Ltd., Oxford, UK)equipped with Magnex gradient set (max. gradient strength 400 mT/m, bore100 mm) interfaced to a Varian DirectDrive console (Varian, Inc., PaloAlto, Calif.) using a volume coil for transmission and surface phasedarray coil for receiving (Rapid Biomedical GmbH, Rimpar, Germany)Isoflurane-anesthetized (1% in 30/70 O2/N2) rats were fixed to a headholder and positioned in the magnet bore in a standard orientationrelative to gradient coils. All MRI data were analyzed using in-housewritten Matlab software. Region of interest analysis was performed foripsilateral hemisphere, lesion core and perifocal area. Values fromcontralateral hemisphere were used as a reference.

Tissue viability and vasogenic edema was determined using absolute T2MRI. Multi-echo multi-slice sequence was used with following parameters;TR=3 s, 6 different echo times (12, 24, 36, 48, 60, 72 ms) and 4averages. Seventeen (17) coronal slices of thickness 1 mm were acquiredusing field-of-view 30×30 mm2 and 256×128 imaging matrix (zero-filled to256×256). In addition to absolute T2, spin density (amount of MRIvisible protons, indicator of vasogenic edema) ratio of ipsi andcontralateral ROI's was determined by extrapolating signal intensity atTE=0 from multiple TE data (intercept of T2 fitting).

For the determination of infarct volume, the same acquired T2-weightedimages were analyzed using in-house written Matlab based software formorphometric measurement. The infarct volume analysis was done by anobserver blinded to the treatment groups.

D_(av) for Cytotoxic Edema

Cytotoxic edema (and its time course) was evaluated also at 24 and 48hours as a control measure using diffusion MRI; the data for calculationof ⅓ of the trace of the diffusion tensor (which is an orientationindependent measure of apparent water diffusion) were acquired using adiffusion weighted Fast Spin-Echo sequence. Following parameters wereused: TR=1.5 s, ETL/TEeff=4/26 ms, b-values 0, 1000×10-3 s/mm2, NT=4.Imaging resolution, slice thickness and slice positioning were keptidentical to absolute T2 MRI acquisition above. 5 slices were acquiredand these were selected from absolute T2 images to best correspond tothe center of lesion in antero-posterior direction.

Contrast Enhanced T1-weighted MRI for BBB Leakage

At 48 hours post-operation, Gadolinium based contrast enhancedT1-weighted MRI was applied to detect blood-brain barrier leakage.Femoral vein was cannulated before the rat was placed into the MRI.Contrast agent was injected as an i.v. bolus (0.5 M Gd-DTPA 0.4 ml/kgi.v. bolus). Pre- and post-contrast agent T1-weighted images wereacquired with 15 min delay to allow proper uptake of the contrast agent.MRI was performed with conventional T1-weighted gradient echo sequencewith identical imaging resolution and slice positioning and withfollowing parameters; TR=0.16 s, TE=5 ms, 70 degree flip and NT=32.Subtraction images (deltaR, post-Gd minus pre-Gd) were produced tohighlight and quantify BBB leakage. Gd-based contrast agents affect theT2 relaxation, thus this MRI component was performed at the very end ofthe MRI session.

Endpoint—Edema Evaluation

After the 48 hour MRI, the rats were decapitated. The brains werequickly removed, cut into ipsi- and contralateral hemispheres that wereweighed for tissue wet weight (edema analysis). Edema % was calculated:[wet weight of ipsilateral hemisphere in mg/wet weight of contralateralhemisphere in mg]×100. Thereafter the brains were fresh-frozen on dryice for possible PK or biochemical purposes. Bbrain tissue wet weightwas found significantly lower in ischemic hemisphere in D91 treatedrats, suggesting that D91 reduces the brain edema after tMCAO.

Inhibition of Protein Tyrosine Phosphatase Beta in a Cell

Disclosed herein are methods for inhibiting protein tyrosine phosphatasebeta (PTP-β) activity in a cell, comprising contacting a cell with aneffective amount of one or more of the disclosed compounds. The cell canbe contacted in vivo, ex vivo, or in vitro.

Compositons

Disclosed herein are compositions which can be used to treat patientswith cancer, wherein the patient having cancer is treated with one ormore anticancer agents that induce vascular leak syndrome in thepatient. As such, disclosed herein are compositions effective inreducing vascular leak resulting from an anticancer treatment, thecompositions comprising an effective amount of one or more of thedisclosed compounds.

In another aspect, disclosed herein are compositions effective fortreating humans or other mammals having a medical condition or diseasestate wherein the treatment for the medical condition or disease stateinduces vascular leak syndrome, the composition comprising:

-   -   a) an effective amount of one or more of the compounds disclosed        herein; and    -   b) one or more pharmaceutical drugs;    -   wherein at least one of the pharmaceutical drugs induces        vascular leak syndrome.

In a further aspect, disclosed herein are compositions comprising;

-   -   a) an effective amount of one or more of the compounds disclosed        herein: and    -   b) one or more chemotherapeutic agents.

Also disclosed herein are compositions which can be used to controlvascular leakage, the compositions comprising an effective amount of oneor more of the compounds disclosed herein. Still further disclosedherein are compositions which can be used to treat patients with aninflammatory disease, non-limiting examples of which include sepsis,lupus, and inflammatory bowel disease, the compositions comprising aneffective amount of one or more of the Tie-2 signaling amplifiersdisclosed herein.

Disclosed herein are compositions which can be used to treat humans orother mammals having vascular leakage due to bacterial or viralinfections, the compositions comprising an effective amount of one ormore of the compounds disclosed herein.

Disclosed herein are compositions comprising one or more of thedisclosed compounds wherein the compositions are useful for treatment ofthe disclosed conditions, illness, injuries, courses of treatment,cellular treatments, and the like.

One aspect relates to a composition comprising:

-   -   a) an effective amount of one or more compounds disclosed        herein; and    -   b) one or more pharmaceutically acceptable ingredients.

Another aspect relates a composition comprising:

-   -   a) an effective amount of one or more compounds disclosed        herein; and    -   b) an effective amount of one or more antiviral or antibacterial        agents;    -   wherein the disclosed compounds and the antiviral or        antibacterial ingredients can be administered together or in any        order.

A further aspect relates to a composition comprising:

-   -   a) an effective amount of one or more compounds disclosed        herein; and    -   b) an effective amount of one or more antibacterial agents        effective against anthrax;    -   wherein the disclosed compounds and the antibacterial        ingredients effective against anthrax can be administered        together or in any order.

A yet further aspect relates to a composition comprising:

-   -   a) an effective amount of one or more compounds disclosed        herein; and    -   b) an effective amount of one or more antiviral agents;    -   wherein the disclosed compounds and the antiviral agents can be        administered together or in any order.

For the purposes of the present disclosure the term “excipient” and“carrier” are used interchangeably throughout the description of thepresent disclosure and said terms are defined herein as, “ingredientswhich are used in the practice of formulating a safe and effectivepharmaceutical composition.”

The formulator will understand that excipients are used primarily toserve in delivering a safe, stable, and functional pharmaceutical,serving not only as part of the overall vehicle for delivery but also asa means for achieving effective absorption by the recipient of theactive ingredient. An excipient may fill a role as simple and direct asbeing an inert filler, or an excipient as used herein may be part of apH stabilizing system or coating to insure delivery of the ingredientssafely to the stomach. The formulator can also take advantage of thefact the compounds of the present disclosure have improved cellularpotency, pharmacokinetic properties, as well as improved oralbioavailability.

The term “effective amount” as used herein means “an amount of one ormore PTP-β inhibitors, effective at dosages and for periods of timenecessary to achieve the desired or therapeutic result.” An effectiveamount may vary according to factors known in the art, such as thedisease state, age, sex, and weight of the human or animal beingtreated. Although particular dosage regimes may be described in examplesherein, a person skilled in the art would appreciated that the dosageregime may be altered to provide optimum therapeutic response. Forexample, several divided doses may be administered daily or the dose maybe proportionally reduced as indicated by the exigencies of thetherapeutic situation. In addition, the compositions of the presentdisclosure can be administered as frequently as necessary to achieve atherapeutic amount.

The disclosed PTP-β inhibitors can also be present in liquids,emulsions, or suspensions for delivery of active therapeutic agents inaerosol form to cavities of the body such as the nose, throat, orbronchial passages. The ratio of PTP-β inhibitors to the othercompounding agents in these preparations will vary as the dosage formrequires.

Depending on the intended mode of administration, the pharmaceuticalcompositions can be in the form of solid, semi-solid or liquid dosageforms, such as, for example, tablets, suppositories, pills, capsules,powders, liquids, suspensions, lotions, creams, gels, or the like,preferably in unit dosage form suitable for single administration of aprecise dosage. The compositions will include, as noted above, aneffective amount of the PTP-β inhibitor in combination with apharmaceutically acceptable carrier and, in addition, can include othermedicinal agents, pharmaceutical agents, carriers, adjuvants, diluents,etc.

For solid compositions, conventional nontoxic solid carriers include,for example, pharmaceutical grades of mannitol, lactose, starch,magnesium stearate, sodium saccharin, talc, cellulose, glucose, sucrose,magnesium carbonate, and the like. Liquid pharmaceutically administrablecompositions can, for example, be prepared by dissolving, dispersing,etc., an active compound as described herein and optional pharmaceuticaladjuvants in an excipient, such as, for example, water, saline aqueousdextrose, glycerol, ethanol, and the like, to thereby form a solution orsuspension. If desired, the pharmaceutical composition to beadministered can also contain minor amounts of nontoxic auxiliarysubstances such as wetting or emulsifying agents, pH buffering agentsand the like, for example, sodium acetate, sorbitan monolaurate,triethanolamine sodium acetate, triethanolamine oleate, etc. Actualmethods of preparing such dosage forms are known, or will be apparent,to those skilled in this art; for example see Remington's PharmaceuticalSciences, referenced above.

Parental administration, if used, is generally characterized byinjection. Injectables can be prepared in conventional forms, either asliquid solutions or suspensions, solid forms suitable for solution orsuspension in liquid prior to injection, or as emulsions. A morerecently revised approach for parental administration involves use of aslow release or sustained release system, such that a constant level ofdosage is maintained. See, e.g., U.S. Pat. No. 3,710,795, which isincorporated by reference herein.

Kits

Also disclosed are kits comprising the compounds be delivered into ahuman, mammal, or cell. The kits can comprise one or more packaged unitdoses of a composition comprising one or more compounds to be deliveredinto a human, mammal, or cell. The unit dosage ampoules or multi-dosecontainers, in which the compounds to be delivered are packaged prior touse, can comprise an hermetically sealed container enclosing an amountof polynucleotide or solution containing a substance suitable for apharmaceutically effective dose thereof, or multiples of an effectivedose. The compounds can be packaged as a sterile formulation, and thehermetically sealed container is designed to preserve sterility of theformulation until use.

The disclosed compounds can also be present in liquids, emulsions, orsuspensions for delivery of active therapeutic agents in aerosol form tocavities of the body such as the nose, throat, or bronchial passages.The ratio of compounds to the other compounding agents in thesepreparations will vary as the dosage form requires.

Depending on the intended mode of administration, the pharmaceuticalcompositions can be in the form of solid, semi-solid or liquid dosageforms, such as, for example, tablets, suppositories, pills, capsules,powders, liquids, suspensions, lotions, creams, gels, or the like,preferably in unit dosage form suitable for single administration of aprecise dosage. The compositions will include, as noted above, aneffective amount of the compounds in combination with a pharmaceuticallyacceptable carrier and, in addition, can include other medicinal agents,pharmaceutical agents, carriers, adjuvants, diluents, etc.

For solid compositions, conventional nontoxic solid carriers include,for example, pharmaceutical grades of mannitol, lactose, starch,magnesium stearate, sodium saccharin, talc, cellulose, glucose, sucrose,magnesium carbonate, and the like. Liquid pharmaceutically administrablecompositions can, for example, be prepared by dissolving, dispersing,etc., an active compound as described herein and optional pharmaceuticaladjuvants in an excipient, such as, for example, water, saline aqueousdextrose, glycerol, ethanol, and the like, to thereby form a solution orsuspension. If desired, the pharmaceutical composition to beadministered can also contain minor amounts of nontoxic auxiliarysubstances such as wetting or emulsifying agents, pH buffering agentsand the like, for example, sodium acetate, sorbitan monolaurate,triethanolamine sodium acetate, triethanolamine oleate, etc. Actualmethods of preparing such dosage forms are known, or will be apparent,to those skilled in this art; for example see Remington's PharmaceuticalSciences, referenced above.

Parental administration, if used, is generally characterized byinjection. Injectables can be prepared in conventional forms, either asliquid solutions or suspensions, solid forms suitable for solution orsuspension in liquid prior to injection, or as emulsions. A morerecently revised approach for parental administration involves use of aslow release or sustained release system, such that a constant level ofdosage is maintained. See, e.g., U.S. Pat. No. 3,710,795, which isincorporated by reference herein.

When the compounds are to be delivered into a mammal other than a human,the mammal can be a non-human primate, horse, pig, rabbit, dog, sheep,goat, cow, cat, guinea pig or rodent. The terms human and mammal do notdenote a particular age or sex. Thus, adult and newborn subjects, aswell as fetuses, whether male or female, are intended to be covered. Apatient, subject, human or mammal refers to a subject afflicted with adisease or disorder. The term “patient” includes human and veterinarysubjects.

While particular embodiments of the present disclosure have beenillustrated and described, it would be obvious to those skilled in theart that various other changes and modifications can be made withoutdeparting from the spirit and scope of the disclosure. It is thereforeintended to cover in the appended claims all such changes andmodifications that are within the scope of this disclosure.

What is claimed is:
 1. A method for determining the course of treatmentfor a subject suffering from vascular leak syndrome, comprising: a)administering to a subject an effective amount of one or more compoundshaving the formula:

wherein R is a substituted or unsubstituted thiazolyl unit having theformula:

R², R³, and R⁴ are each independently: i) hydrogen; ii) substituted orunsubstituted C₁-C₆ linear, branched, or cyclic alkyl; iii) substitutedor unsubstituted C₂-C₆ linear, branched, or cyclic alkenyl; iv)substituted or unsubstituted C₂-C₆ linear or branched alkynyl; v)substituted or unsubstituted C₆ or C₁₀ aryl; vi) substituted orunsubstituted C₁-C₉ heteroaryl; vii) substituted or unsubstituted C₁-C₉heterocyclic; or viii) R² and R³ can be taken together to form asaturated or unsaturated ring having from 5 to 7 atoms; wherein from 1to 3 atoms can optionally be heteroatoms chosen from oxygen, nitrogen,and sulfur; Z is a unit having the formula:-(L)_(n)-R¹ R¹ is chosen from: i) hydrogen; ii) hydroxyl; iii) amino;iv) substituted or unsubstituted C₁-C₆ linear, branched or cyclic alkyl;v) substituted or unsubstituted C₁-C₆ linear, branched or cyclic alkoxy;vi) substituted or unsubstituted C₆ or C₁₀ aryl; vii) substituted orunsubstituted C₁-C₉ heterocyclic rings; or viii) substituted orunsubstituted C₁-C₉ heteroaryl rings; L is a linking unit having theformula:-[Q]_(y)[C(R^(5a)R^(5b))]_(x)[Q¹]_(z)[C(R^(6a)R^(6b))]_(w)— Q and Q¹ areeach independently: i) —C(O)—; ii) —NH—; iii) —C(O)NH—; iv) —NHC(O)—; v)—NHC(O)NH—; vi) —NHC(O)O—; vii) —C(O)O—; viii) —C(O)NHC(O)—; ix) —O—; x)—S—; xi) —SO₂—; xii) —C(═NH)—; xiii) —C(═NH)NH—; xiv) —NHC(═NH)—; or xv)—NHC(═NH)NH—; R^(5a) and R^(5b) are each independently: i) hydrogen; ii)hydroxy; iii) halogen; iv) C₁-C₆ substituted or unsubstituted linear orbranched alkyl; or v) a unit having the formula:—[C(R^(7a)R^(7b))]_(t)R⁸ R^(7a) and R^(7b) are each independently: i)hydrogen; or ii) substituted or unsubstituted C₁-C₆ linear, branched, orcyclic alkyl; R⁸ is: i) hydrogen; ii) substituted or unsubstituted C₁-C₆linear, branched, or cyclic alkyl; iii) substituted or unsubstituted C₆or C₁₀ aryl; iv) substituted or unsubstituted C₁-C₉ heteroaryl; or v)substituted or unsubstituted C₁-C₉ heterocyclic; R^(6a) and R^(6b) areeach independently: i) hydrogen; or ii) C₁-C₄ linear or branched alkyl;the index n is 0 or 1; the indices t, w and x are each independentlyfrom 0 to 4; the indices y and z are each independently 0 or 1; or apharmaceutically acceptable salt thereof; and b) monitoring the bloodplasma level of angiopoietin-2 in the subject; wherein administering ofthe one or more compounds stops when the level of angiopoietin-2 in theblood plasma of the subject is from about 1 ng/mL to about 2 ng/mL. 2.The method according to claim 1, wherein the compound has the formula:

or a pharmaceutically acceptable salts thereof.